REVIEW published: 06 September 2019 doi: 10.3389/fnagi.2019.00236 The Involvement of Peripheral and Brain Insulin Resistance in Late Onset Alzheimer’s Dementia Jaume Folch 1,2,3 , Jordi Olloquequi 4 , Miren Ettcheto 1,3,5,6 , Oriol Busquets 1,3,5,6 , Elena Sánchez-López 3,7,8 , Amanda Cano 3,7,8 , Triana Espinosa-Jiménez 3,5,6 , Maria Luisa García 3,7,8 , Carlos Beas-Zarate 9 , Gemma Casadesús 10 , Mónica Bulló 1,10 , Carme Auladell 3,6,11 and Antoni Camins 3,5,6 * 1 Department of Biochemistry and Biotechnology, Faculty of Medicine and Health Sciences, University Rovira i Virgili (URV), Reus, Spain, 2 Institute of Health Pere i Virgili, IISPV , Reus, Spain, 3 Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Institute of Health Carlos III, Madrid, Spain, 4 Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Talca, Chile, 5 Departament de Farmacologia, Toxicologia i Química Terapèutica, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, Barcelona, Spain, 6 Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain, 7 Unitat de Farmàcia, Tecnologia Farmacèutica i Fisico-Química, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, Barcelona, Spain, 8 Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain, 9 Laboratorio de Regeneración y Desarrollo Neural, Departamento de Biología Celular y Molecular, Instituto de Neurobiología, CUCBA, Guadalajar, México, 10 Department of Biological Sciences, Kent State University, Kent, OH, United States, 11 Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Institute of Health Carlos III, Madrid, Spain Edited by: Raymond Chuen-Chung Chang, The University of Hong Kong, Nowadays, Alzheimer’s disease (AD) is a severe sociological and clinical problem. Hong Kong Since it was first described, there has been a constant increase in its incidence and, Reviewed by: for now, there are no effective treatments since current approved medications have Agata Copani, only shown short-term symptomatic benefits. Therefore, it is imperative to increase University of Catania, Italy Alasdair Barr, efforts in the search for molecules and non-pharmacological strategies that are capable University of British Columbia, of slowing or stopping the progress of the disease and, ideally, to reverse it. The Canada amyloid cascade hypothesis based on the fundamental role of amyloid has been the *Correspondence: central hypothesis in the last 30 years. However, since amyloid-directed treatments Antoni Camins camins@ub.edu have shown no relevant beneficial results other theories have been postulated to explain the origin of the pathology. The brain is a highly metabolically active energy- Received: 30 April 2019 consuming tissue in the human body. It has an almost complete dependence on the Accepted: 15 August 2019 Published: 06 September 2019 metabolism of glucose and uses most of its energy for synaptic transmission. Thus, Citation: alterations on the utilization or availability of glucose may be cause for the appearance Folch J, Olloquequi J, Ettcheto M, of neurodegenerative pathologies like AD. In this review article, the hypothesis known Busquets O, Sánchez-López E, Cano A, Espinosa-Jiménez T, as Type 3 Diabetes (T3D) will be evaluated by summarizing some of the data that García ML, Beas-Zarate C, has been reported in recent years. According to published research, the adherence Casadesús G, Bulló M, Auladell C over time to low saturated fatty acids diets in the context of the Mediterranean diet and Camins A (2019) The Involvement of Peripheral and Brain would reduce the inflammatory levels in brain, with a decrease in the pro-inflammatory Insulin Resistance in Late glial activation and mitochondrial oxidative stress. In this situation, the insulin receptor Onset Alzheimer’s Dementia. Front. Aging Neurosci. 11:236. pathway would be able to fine tune the mitochondrial biogenesis in neuronal doi: 10.3389/fnagi.2019.00236 cells, regulation the adenosine triphosphate/adenosine diphosphate intracellular Frontiers in Aging Neuroscience | www.frontiersin.org 1 September 2019 | Volume 11 | Article 236 Folch et al. Brain Insulin Resistance in Alzheimer’s balance, and becoming a key factor involved in the preservation of the synaptic connexions and neuronal plasticity. In addition, new targets and strategies for the treatment of AD will be considered in this review for their potential as new pharmacological or non-pharmacological approaches. Keywords: insulin resistance, obesity, type 2 diabetes mellitus, Alzheimer’s disease, Mediterranean diet, neuroinflammation and neurodegeneration INTRODUCTION et al., 2016; Kandimalla et al., 2017; Kang et al., 2017; Tong et al., 2017). This concept describes a brain-specific pathological Several theories have been in the headlines of the Alzheimer’s situation in which insulin and IGF resistance is developed disease (AD) research scene in the last 10 years (Folch et al., inducing cognitive impairments and neurodegeneration. Insulin 2013; Alzheimer’s Association, 2016; Dobson, 2017; Hurtado- resistance is classically defined as the state in which high Puerto et al., 2018) and, in many of them, it was postulated how levels of circulating insulin (hyperinsulinemia) are associated to an alteration in a metabolic mechanism runs in parallel, or is hyperglycemia, concept that has been extended to other tissues the cause, for the development of the classical features of AD and organs which show reduced activation of the pathways in (Frölich et al., 2015). Eventually, it has led to the understanding insulin signaling. Therefore, AD and diabetic pathologies share that pathologies like type 2 Diabetes Mellitus (T2DM) and AD, several common features (Willette et al., 2015), situation in which or conditions like morbid obesity, previously believed to run adherence to good life habits, especially in terms of motor activity independently, are actually highly connected through specific and diet, may have beneficial effects on cognitive processes molecular interactions that evolve in the same direction (de la during aging in humans. Monte, 2012; De Felice et al., 2014). From a metabolic outlook, the brain requires a high amount of Despite the hypotheses focus on amyloid and TAU energy to maintain its functions, especially for the transmission phosphorylation have dominated the neuropathology of of synaptic impulses (Yun and Hoyer, 2000; Hoyer, 2004; Maurer AD so far, new theories have come to light, in part, due to the and Hoyer, 2006). Hence, alterations in brain glucose metabolism failure of all the developed drugs directed against molecules lead to severe dysregulations in cellular function. For example, related to the amyloidogenic pathway (Gauthier et al., 2016). a decrease in ATP production and choline acetyltransferase It has been described that this failure may be the result of activity in presynaptic cholinergic neurons reduce the availability the complex etiology of AD. As of now, it could be classified of acetylcholine in the brain which is worsened by the depletion into two subgroups. On the one hand, familial AD in which of citric acid cycle intermediates that are also required for the genetic alterations of the amyloid precursor protein (APP) synthesis of this neurotransmitter (Hoyer, 2002a,b; Salkovic- or presenilin-1 (PS-1) are involved, accounting the 3% of Petrisic et al., 2009). Alterations on its availability could also cases of the disease. On the other hand, representing the trigger a dysfunction in synaptic transmission and affect proper remaining 97%, the late onset form of AD (LOAD) which is cognitive function (Hoyer, 2004; Frölich et al., 2015; Fadel and associated with advanced age, mutations of the apolipoprotein E Reagan, 2016). (APOE) ε4 allele, hypertension and hyperlipidaemia, as well This review article focuses on the evidence concerning as with coronary disease, T2DM and obesity among other less the effects of obesity and T2DM in the process of cognitive determinant factors. loss. Likewise, we discuss throughout the manuscript the In parallel with AD, obesity has become pandemic in the close relationship between alterations at the peripheral level Western world and it has shown increased prevalence in most related to obesity that may favor the risk of developing AD countries mainly due to changes in nutritional habits and and the role of amyloid-β (Aβ) generated at the brain level, lifestyle (de la Monte, 2014; Luciano et al., 2015; Kivipelto et al., which could be an inducer of the onset of T2DM. Since 2018). Although the interaction between obesity, aging and AD obesity and metabolic syndrome are modifiable risk factors that is a complex process, there are evidences demonstrating that contribute to insulin-resistant diabetes, special emphasis will be obesity and metabolic dysfunctions in middle age substantially put on their relationship with T3D. Finally, pharmacological increase the risk of developing AD (Kivipelto et al., 2018). and environmental interventions, such a suitable diet, will also Thus, studies conducted in the last 20 years support the be discussed as possible strategies to prevent obesity-related hypothesis that deficits in brain insulin and insulin-like growth cognitive loss. factor (IGF-1) signaling mediate cognitive impairment and neurodegeneration in AD (de la Monte, 2012). As we will PHYSIOLOGICAL ROLE OF INSULIN discuss below, the main role of insulin and insulin receptor BEYOND PERIPHERAL TISSUES pathway in different brain regions as hippocampus and cortex is mainly related to the maintenance of intracellular energy As we mentioned, the classical amyloid and Tau hypotheses of levels needed to sustain synaptogenesis and neuronal plasticity. AD have been challenged by reported evidence that describes For this reason, some researchers have even referred to AD how they may not be the source for the pathology in its as Type 3 Diabetes (T3D; de la Monte, 2012, 2014; Chami late onset form (Selkoe and Hardy, 2016). It was Dr. Hoyer Frontiers in Aging Neuroscience | www.frontiersin.org 2 September 2019 | Volume 11 | Article 236 Folch et al. Brain Insulin Resistance in Alzheimer’s who in 1985 introduced the idea of alterations in brain of hypertriglyceridemia. In agreement with this, Obici and co- metabolism as the source for the appearance of LOAD through workers demonstrated that a decrease in the hypothalamic IR defects in the oxidative degradation of glucose (Hoyer, 2004; expression is enough to induce several key features of metabolic Frölich et al., 2015; Morgen and Frölich, 2015). Specifically, syndrome (Obici, 2009). Hence, insulin resistance in the brain it has been described that oxidative dysregulation triggers would be involved in the pathophysiology of obesity and T2DM cellular downstream signaling pathways promoting neuronal in the peripheral tissues. degeneration through the induction of stress in organelles like the All these experimental data indicate that brain IR plays mitochondria and the endoplasmic reticulum. As a consequence, a key role in: (i) regulation of cognitive processes through Aβ and Tau alterations would emerge contributing to the hippocampal IR; and (ii) regulation of peripheral glucose ongoing cognitive loss. This could explain why drugs focusing metabolism. Consequently, restoration of normal insulin levels on Aβ and Tau have proven useless so far since they would be and prevention of brain insulin resistance may be a therapeutic targeting a consequence or aggravator of the pathology but not strategy for delaying cognitive loss in AD (Biessels, 2013; its root. Ramalingam and Kim, 2014). In addition to this, in recent years it has been demonstrated that insulin receptors (IRs) and their ligand hormone play a TOWARDS BRAIN INSULIN RESISTANCE more relevant role in the brain than was previously thought. IN LATE ONSET AlZHEIMER’S DISEASE Specifically, several studies have reported presence of IRs in hippocampus, cerebral cortex, cerebellum and choroidal Recently, Castellani et al. (2019) proposed, in an excellent review plexus of the mammalian brain (Hoyer, 2004; de la Monte on AD therapeutics, that it was very reasonable to conclude et al., 2006) and especially in postsynaptic terminals (Abbott that the amyloidogenic pathway is very closely related to AD, et al., 1999). It has been demonstrated that insulin levels however, the important role of other players was suggested become strongly reduced in these regions during aging and into the origin of the pathology since the clearance of Aβ in sporadic AD (Ramalingam and Kim, 2014). Indeed, insulin protein was not enough to modify the evolution of the disease. is preferentially transported to the brain through the blood- Furthermore, pharmacological strategies targeting Aβ-related brain barrier (BBB) in a receptor-mediated mechanism and biomarkers like BACE1 inhibitors or anti-Aβ antibodies, have its availability is critical for the activation of brain IR. In failed to cure or halt LOAD (Cummings et al., 2018). Hence, this aspect, it has been proposed that brain insulin has a new strategies should be designed to complement the actual neuroprotective capacity against the accumulation of senile therapeutic proposals that, so far, have been mainly focused on plaques, by regulating Aβ peptide levels and preventing the the amyloid hypothesis. binding of Aβ oligomers to synapses (Zhao et al., 2008; One of the first reviews that criticized the paradigm of De Felice et al., 2009, 2014; Lyra E Silva et al., 2019). the amyloid cascade overactivation as the origin of AD was Interestingly, AD preclinical models show that preventing IR written by one of the co-authors that first described this central inhibition enhances Protein kinase B (AKT) signaling, which is hypothesis (Cleary et al., 2005; Hardy, 2009; Selkoe and Hardy, involved in cell proliferation, cell growth, protein synthesis and 2016). But, back in 1985, as it was previously mentioned, before inhibition of apoptosis, but also in the hyperphosphorylation the installment of the amyloidogenic hypothesis, Dr. Siegfried of Tau through the control of the glycogen synthase kinase 3β Hoyer had already proposed the concept of central insulin (GSK3β; El Khoury et al., 2014). By contrast, insulin deficits resistance and altered insulin signaling in LOAD (Frölich et al., have been linked to the inhibition of several phosphatases 2015; Hoyer, 2002b, 2004; Morgen and Frölich, 2015). Later on, involved in Tau dephosphorylation (El Khoury et al., 2014). Dr. de la Monte published a series of articles about the metabolic Finally, it has been proven that insulin signaling pathway hypothesis of AD, and became one of the main defenders is also involved in the modulation of neuroinflammatory of the so-called ‘‘brain insulin resistance’’ or T3D hypothesis processes and vascular inflammation (Chen and Zhong, 2013). (de la Monte et al., 2006; de la Monte and Wands, 2008; Likewise, insulin modulation acts through the mitogen-activated Chami et al., 2016; de la Monte, 2017). In these experiments, protein kinase (MAPK) pathway, which plays an important the intracerebral administration of streptozotocin (STZ) was role in cell differentiation, cell proliferation, apoptosis as well used as an experimental model to induce LOAD-like cognitive as inflammation. As we will discuss below, the activation impairments in rodents, allowing to study this theory deeper of some c-JUN N-terminal Kinases (JNKs) should be a (de la Monte et al., 2006; Correia et al., 2011; Salkovic-Petrisic key factor linking insulin signaling to synaptogenesis failure et al., 2013; Tong et al., 2017). The research by Dr. de la Monte (Huang et al., 2017; Pomytkin et al., 2018). in AD patients also proved significant reductions in insulin and In 2000, Bru and co-workers published an interesting article IGF-1 receptor levels in the frontal cortex, hippocampus, and demonstrating that brain IR is involved in the metabolic control hypothalamus (Steen et al., 2005), reinforcing the idea of T3D. of peripheral tissues through the generation of a murine model Likewise, Cardoso et al. (2017) suggested the term ‘‘diabesity’’ to with a specific deletion of the neuronal IR gene (NIRKO mice; explain the presence of both metabolic and cognitive affectations. Bru et al., 2000). This inactivation resulted in insulin resistance In parallel with these observations, results from epidemiologic at the central nervous system (CNS) but mice also developed studies contributed to reinforce the proposed concept obesity, combined with hyperphagia, an increase of leptin and of T3D. Doubtlessly, one of the most important is the insulin concentrations in plasma, as well as the development Rotterdam’s study (Ott et al., 1999; Schrijvers et al., 2010; Frontiers in Aging Neuroscience | www.frontiersin.org 3 September 2019 | Volume 11 | Article 236 Folch et al. Brain Insulin Resistance in Alzheimer’s Luciano et al., 2015). This project has investigated the connection ISF Aβ (Macauley et al., 2015; Stanley et al., 2016). In turn, between T2DM and LOAD for almost a decade, revealing that Grillo et al. (2015) reported that the administration of viral those patients diagnosed with T2DM had higher risk of vectors expressing an antisense sequence of the rat brain IR developing dementia. Subsequent clinical and epidemiological caused cognitive impairments. Thus, they generated a specific rat studies have confirmed this association, by demonstrating model of altered brain insulin signaling associated to cognitive that alterations of metabolic parameters related to glucose loss. These results are of great relevance since demonstrated that metabolism were associated with cognitive loss (Talbot et al., selective insulin resistance at the hippocampal level contributes 2012; Biessels, 2013; Walker and Harrison, 2015). Moreover, directly to the development of cognitive deficits observed in in a clinical study in patients with AD and hyperinsulinemia, patients with metabolic disorders such as T2DM and obesity Willette et al. (2015) demonstrated that insulin resistance (Fadel and Reagan, 2016). increased the number of Aβ depositions in the brain. It has Finally, among other risk factors likely to favor the also been reported that neurons from AD patients exhibit an development of sporadic AD, the mutation of the APOE4 allele insulin mRNA expression four times lower than normal in has recently shown an intriguing association with insulin the hippocampus and two times lower than normal in the resistance. Thus, it has been suggested that APOE4 impairs IR hypothalamus (Chen and Zhong, 2013). This situation would trafficking by trapping it in endosomes, leading to impaired be aggravated by the disruption of the activity of astrocytes insulin signaling (Zhao et al., 2017). The APOE gene ε4 allele is forming the BBB. Likewise, patients with AD show alterations so far considered the strongest genetic risk factor for AD. These in the transport of this hormone into the brain (Molofsky et al., findings are relevant to explain the correlation between T2DM 2012; An et al., 2018). It is noteworthy to point out that, in and LOAD (Peila et al., 2002). In addition, this implies that the addition to the lower availability of insulin in the brain, cerebral presence of APOE4 allele and T2DM could act synergistically in insulin resistance is another pathophysiological feature of AD. AD pathogenesis. Accordingly, the highest risk for AD and the Thus, it seems that insulin signaling could have a key role in most severe neuropathology is found in individuals with both cognitive loss. diabetes and the APOE4 mutation (Peila et al., 2002). In 2014, the Hisayama’s study showed, through the analysis of microarrays, modifications in the normal expression of genes OBESOGENIC DIET AS A RISK FACTOR related to T2DM in AD brains, especially in the hippocampus FOR COGNITIVE IMPAIRMENT (Hokama et al., 2014). More recent studies have also reinforced the notion of an insulin resistance having a key role in Previous studies reported that obesity is associated to memory AD’s pathogenesis. For instance, An et al. (2018) reported a impairment through insulin resistance in both, young people strong association between impairments in glucose metabolism (Cheke et al., 2016) and cognitively normal older people and increased glucose concentrations in areas sensible to Aβ although the underlying mechanisms remain unclear (Hargrave deposition and neurofibrillary pathology. The authors suggested et al., 2016; Kivipelto et al., 2018). Likewise, in the older that AD is associated with a failure in neuronal glucose people an association between obesity and brain atrophy has utilization, which is mediated by an alteration in glycolysis. The been described (Raji et al., 2010). It is widely accepted that authors argued that three enzymes involved in the glycolysis obesity favors the emergence of metabolic syndrome affecting (hexokinase, phosphofructokinase, and pyruvate kinase) showed peripheral tissues such as liver, pancreas and adipocytes (Cardoso significant reduction in their activity in AD. In turn, in the et al., 2017; Kang et al., 2017; Kothari et al., 2017). We have Whitehall II clinical study, Singh-Manoux et al. (2018) reported already discussed the observations based on the experimental that obesity (BMI >30 kg/m2 ) at 50 years of age is a risk factor use of STZ to induce diabetes in rats (de la Monte et al., for AD. However, the association decreased with increasing 2006; de la Monte, 2017). This toxic compound can trigger age, indicating that this association is modified by age and Type 1 diabetes mellitus by killing insulin-producing cells in obesity, being midlife obesity the riskiest stage for dementia the pancreas and, at lower doses, can lead to T2DM and (Singh-Manoux et al., 2018). In another interesting clinical study, related alterations (Correia et al., 2011; Salkovic-Petrisic et al., Ahmed et al. (2017) reported a bidirectional association between 2013; Tong et al., 2017). Indeed, lower STZ doses have been T2DM and LOAD. Besides, they reported that Memantine—a involved in neuronal loss, neuroinflammation, oxidative stress drug which is currently used in AD treatment- showed an and accumulations of phospho-TAU and Aβ in cortical-limbic ameliorating effect on T2DM. This is in accordance with structures that characteristically degenerate in AD, leading to results published by our research group and others, where impaired spatial learning and memory (Correia et al., 2011). the benefits of Memantine administration were demonstrated Since STZ is a nitrosamine, a chemical compound that can in a mixed murine model of T2DM and AD (Sato and be found in many foods and other consumables, the question Morishita, 2013; Shinohara and Sato, 2017; Ettcheto et al., 2018b; is: could diet be directly involved in the exacerbation of Deng et al., 2019). cognitive decline in LOAD? Indeed, several studies suggest Regarding other preclinical studies, have been shown that that environmental exposure to food additives may play a hyperglycemia raises Aβ levels in the interstitial fluid (ISF) by critical role in the pathogenesis of AD (de la Monte et al., altering neuronal activity. It seems that high glucose metabolism 2018, 2019). In light of the unstoppable increase in LOAD can alter ATP-sensitive potassium (KATP) channels, which are prevalence rates and the widespread use of nitrites and the link between changes in metabolism, neuronal activity and nitrates in foods and agricultural products over the past Frontiers in Aging Neuroscience | www.frontiersin.org 4 September 2019 | Volume 11 | Article 236 Folch et al. Brain Insulin Resistance in Alzheimer’s 30–40 years, the impact of exposure to dietary components et al., 2017). For instance, Chua et al. (2012) demonstrated that a as nitrosamines should be reviewed in relation to T3D reduction in insulin signaling usually precedes the accumulation (de la Monte et al., 2018). of Aβ peptide in APP/PS1 mice. In another study developed Several studies suggest that there is a link between calorie by our research group, long-term exposure to HFD favored the intake from diets rich in saturated fats or high fat diets (HFD) appearance of Aβ depositions in the brain of C57BL/6J mice and the resulting obesity and cognitive deficits (Kohjima et al., (Busquets et al., 2017). This is an intriguing observation because, 2010; Yarchoan et al., 2014; Pratchayasakul et al., 2015; Moser since these wild-type mice do not develop cognitive loss per se, and Pike, 2017; Sah et al., 2017). By contrast, moderate dietary our results implied that HFD maintained for a long time could restriction has been found to improve cognition and, indeed, be enough to damage brain. Moreover, HFD caused alterations in life expectancy (Parrella et al., 2013). These findings are the different cell processes, such as normal autophagy and apoptosis, reason why studies on the interaction metabolism-AD have and also enhanced an inflammatory reaction that leads to a gained a great deal of interest. Thus, it is not surprising that HFD decrease in the neuronal precursor cells (Busquets et al., 2017). has been associated with a large number of metabolic diseases, Taken altogether, the above-mentioned results reinforce the such as obesity, systemic insulin resistance, metabolic syndrome hypothesis of a metabolic etiology of AD in its sporadic and late and T2DM (de la Monte, 2014; Ferreira et al., 2014; Cardoso onset form. They also confirm that HFD favors Aβ depositions in et al., 2017). Nuzzo et al. (2015) provided evidence that obesity the brain, a key feature of this disease. In this point, an important and insulin resistance are involved to inflammation, adipokine question arises: what is the molecular link between diet, T2DM dyshomeostasis, oxidative stress and mitochondrial dysfunction, and cognitive impairment? In this regard, Osborne et al. (2016) all of them being mechanisms that favor neurodegeneration. In reported that intrahippocampal infusion of an Aβ33–42 gamma those experiments, mice fed with an HFD showed elevated levels antibody reversed cognitive impairment in rats with HFD-related of APP and Aβ40/Aβ42, BACE, GSK3β and TAU proteins, all cognitive loss. Hence, these results stressed the role of soluble Aβ involved in APP processing and Aβ accumulation. In light of in obesity-mediated cognitive loss and they are in agreement with these results, it is clear that the exposure of rodents to a HFD previous studies hypothesizing that diffusible Aβ oligomers are damages their brain in a similar manner to the hallmarks of responsible for neural dysfunction leading to AD (Walsh et al., AD (Pratchayasakul et al., 2015; Ettcheto et al., 2016; Sah et al., 2005; Tarasoff-Conway et al., 2015; Xia et al., 2016; Bu et al., 2018; 2017). In another study, Bocarsly et al. (2015) also reported Hurtado-Puerto et al., 2018). Accordingly, Aβ could be a possible negative consequences of HFD in rats. Specifically, HFD has connection between the metabolic and the classical amyloid been associated to alterations in brain cortical dendritic spines hypotheses of AD, since it binds to the IR and may trigger and a decrease in presynaptic and postsynaptic protein levels, its internalization at the post-synaptic level, thereby blocking which was related to behavioral cognitive deficits in working glutamatergic neurotransmission (De Felice et al., 2014; Ribe and memory and cognition (Bocarsly et al., 2015). In turn, Kothari Lovestone, 2016; Ahmed et al., 2017). In addition, Aβ oligomers and colleagues reported that HFD may impair brain insulin have been found to inactivate IRs via the JNKs pathway through signaling promoting neuroinflammation, formation of Aβ a mechanisms that is comparable to the established peripheral plaques and neurofibrillary tangles, as well as loss of synaptic effect of JNKs on IRs in T2DM (Zhao et al., 2008; Ma et al., 2009; plasticity (Sallam et al., 2015). In the same line, Kohjima et al. Freiherr et al., 2013; Lyra E Silva et al., 2019). (2010) also reported that diet-induced insulin resistance is associated with reduced neuronal insulin receptor signaling, leading to an increase in Aβ levels and cognitive loss in the WHICH CAME FIRST: OBESITY OR Aβ? brain of Tg2576 mice. Likewise, an hypercaloric diet increases THE “CHICKEN OR THE EGG” CAUSALITY brain Aβ levels and cognitive alterations in APPswe/PS1dE9 DILEMMA IN LOAD (APP/PS1) mice (Petrov et al., 2015). Similarly, the same murine model under a HFD at an early pre-symptomatic disease Among the plethora of functions performed by the CNS, it also stage (3 months old) showed an increase in Aβ1–42 peptide, plays a key role in the glucose homeostasis. Indeed, different a decrease in Protein Kinase A (PKA) levels and alterations in glucose sensors signals are integrated and processed by the CNS, the c-AMP Response Element Binding (CREB)/N-methyl-D- involved in regulating glucose production, pancreatic hormonal aspartate receptor 2B (NMDAR2B)/Peroxisome proliferator- secretion and glucose uptake, maintaining the balanced glucose activated receptor gamma coactivator 1-alpha (PGC-1α) levels against changing conditions (Cai, 2013; Zheng et al., 2018). pathway (Sheng et al., 2012; Ettcheto et al., 2016; Katsouri The hypothalamus controls several regulatory mechanisms of et al., 2016; Wang et al., 2017). This mechanism involves peripheral glucose homeostasis through the control of various the attenuation of the forkhead-like transcription factor 1 signals from organs and tissues involved in digestion, absorption (FoxO3a) expression. and storage of nutrients. Neurons responsible for the CNS There can be found some other several preclinical studies metabolic balance are found in a sub-region of the ventromedial in which the exposure to HFD is associated with a decline hypothalamus, called the arcuate nucleus (aRC). They express in cognitive function. In many of these studies, HFD-induced anabolic peptides such as the neuropeptide Y and agouti- alterations in peripheral insulin sensitivity lead to a central related peptide (aGRP), as well as proopiomelanocortin, which insulin resistance and biochemical changes related to increased is the precursor of numerous biologically active peptides, Aβ deposition and neurofibrillary tangle formation (Kothari including the α-melanocyte stimulating hormone (αMSH) which Frontiers in Aging Neuroscience | www.frontiersin.org 5 September 2019 | Volume 11 | Article 236 Folch et al. Brain Insulin Resistance in Alzheimer’s favors catabolism (Obici et al., 2002; Obici, 2009; Sandoval T2DM pathophysiology (Kuo et al., 2000; Shinohara and Sato, et al., 2009). This complex machinery includes hormones 2017). In any case, some recent studies have provided data like insulin, adipokines as leptin, molecules like ghrelin or on the complex mechanistic interactions between T2DM and gut peptides as Glucagon-like peptide-1 (GLP-1) and glucose- AD. For instance, Plucińska et al. (2016) demonstrated, using a dependent insulinotropic polypeptide (GIP; De Felice et al., neuron-specific human BACE1 knock-in mouse model (PLB4) 2014; Fasshauer and Blüher, 2015). Insulin decreases blood that increased neuronal BACE1 is sufficient to alter systemic glucose concentrations by suppressing glucose production and glucose metabolism. Therefore, this study also confirms that upregulating its absorption by peripheral tissues (such as skeletal brain Aβ leads to a peripheral T2DM process. In turn, Sallam muscles and fat). Leptin exerts anorexigenic effect when it is and colleagues developed an adipocyte-specific ecto-nucleotide released from fat tissue, whereas GLP1 and GIP are secreted pyrophosphate phosphodiesterase over-expressing transgenic from the pancreas during feeding inducing the increase glucose- (AtENPP1-Tg) as metabolic syndrome and systemic insulin dependent insulin secretion. However, the CNS also produces resistance animal model (Sallam et al., 2015). These mice showed some of these molecules and receptors, which can be found in changes in lipid composition of hippocampal synaptosomes, many of its areas including the aRC. Surprisingly, in addition to impaired basal synaptic transmission as well as down-regulation be capable of trespassing the BBB, insulin can also be secreted of IR expression. The authors concluded that hippocampal autonomously by the brain (Warren et al., 2012; Folch et al., 2013; molecular and functional integrity become affected by the Nuzzo et al., 2015). IR and lipid composition, describing a potential mechanism In light of the above-mentioned, it is crucial to understand the responsible for the cognitive impairments associated with potential mechanisms linking AD to obesity and T2DM. Among metabolic syndrome (FFA) and T2DM (Sallam et al., 2015). the hypotheses suggested, there is mounting data supporting an Therefore, the process of cognitive impairment could start early involvement of Aβ-mediated alterations in hypothalamus in peripheral tissues or, at least, could be exacerbated by leading to peripheral metabolic dysregulation. This may occur potential interactions between peripheral tissues and brain. even before the appearance of cognitive loss symptoms. In Excessive caloric intake leads to hypertrophy or hyperplasia this line of thought, Arrieta-Cruz and colleagues reported that of adipocytes, resulting in adipose tissue expansion. As a direct administration of Aβ25–35 in the hypothalamus disrupts consequence, there is an increased secretion of adipokines, the regulation of glucose oxidation (Arrieta-Cruz et al., 2015; including a broad range of cytokines and chemokines, triggering Arrieta-Cruz and Gutiérrez-Juárez, 2016). In turn, Clarke and the recruitment of inflammatory cells to the tissue and a second colleagues also reported that intracerebroventricular injections wave of inflammatory mediators release (Fasshauer and Blüher, of Aβ oligomers trigger peripheral systemic glucose intolerance 2015). Among these mediators, TNFα and some angiogenic and insulin resistance in rodents, through a process related with factors could inhibit peripheral insulin signaling. Additionally, hypothalamic inflammation (Clarke et al., 2015, 2018; Lourenco other proinflammatory cytokines such as interleukin IL1b et al., 2019). Hence, these data reinforce the notion that Aβ affects and IL6, are able to cross the BBB and exacerbate brain hypothalamic function, altering peripheral metabolic control and inflammation together with proinflammatory factors produced whole-body homeostasis (Obici et al., 2002; Sandoval et al., 2009; by microglial cells (Warren et al., 2012; Fasshauer and Blüher, Figure 1). Likewise, cerebral Aβ could traverse the BBB and 2015). In turn, high blood insulin concentrations trigger affect peripheral tissues, leading to peripheral insulin resistance. an excessive release of FFA from adipocytes to liver and In accordance, it has been demonstrated that plasma Aβ induces muscles, leading to exacerbated inflammatory responses and insulin resistance in hepatocytes by activating Janus Kinase 2 increased accumulation of Aβ. By contrast, hyperinsulinemia (JAK2)/STAT3/Suppressor of Cytokine Signaling-1 (SOCS-1) decreases insulin transport into the brain. Thus, adipose signaling pathway in APP/PS1 mice, suggesting an important tissue extension in obesity and T2DM could trigger cognitive role of peripheral Aβ in the regulation of glucose metabolism loss, reflecting the relationship between the adipose tissue (Zhang et al., 2013). Moreover, Aβ accumulation also occurs in and the brain, thus impacting on its function (Fasshauer the pancreas and skeletal muscle which may induce alterations and Blüher, 2015). Conversely, hypothalamic soluble Aβ and on peripheral glucose metabolism (Roher et al., 2009; Miklossy Tau phosphorylation may contribute to the impairment of et al., 2010; Kulas et al., 2017). Likewise, peripheral tissues the control of peripheral glucose metabolism in patients such as heart, liver, testis, aorta, lung, intestines, skin, as well with AD (Cai, 2013; Chen and Zhong, 2013). This could as the adrenal, salivary, and thyroid glands also produced Aβ be mediated by a direct effect of Aβ on central IR and peptide (Wang et al., 2017; Wijesekara et al., 2017). Although the by a mechanism mediated by Tau hyperphosphorylation, implications of peripheral Aβ are still unknown, a contribution which increases intraneuronal insoluble insulin aggregates and of a dynamic maintenance of Aβ levels throughout the body downregulates IRs, leading to insulin resistance (El Khoury et al., should not be discarded (Selkoe and Hardy, 2016; Bu et al., 2018). 2014; Marciniak et al., 2017; Rodriguez-Rodriguez et al., 2017; Indeed, platelets are a peripheral source of APP and they are able Gonçalves et al., 2019). to generate Aβ in a similar manner than neurons, skin fibroblasts, Finally, a study performed by Banks et al. (2018) introduced skeletal muscles and cerebrovascular smooth muscle cells (Roher an additional mechanism whereby metabolic syndrome et al., 2009). Hence, peripheral alterations in APP metabolism contributes to cognitive impairment. The authors reported might constitute a systemic and also a CNS problem in LOAD, that triglycerides cross the BBB leading to brain leptin and hypothesizing that these peripheral Aβ could also contribute to insulin receptors resistance, which has a negative effect on Frontiers in Aging Neuroscience | www.frontiersin.org 6 September 2019 | Volume 11 | Article 236 Folch et al. Brain Insulin Resistance in Alzheimer’s FIGURE 1 | Obesity, caused by a sedentary life or a high fat diet, increases the risk of type 2 Diabetes Mellitus [T2DM; Metabolic hypothesis of Alzheimer’s disease (AD)]. This condition increases the risk of cognitive loss and AD through mitochondrial alteration, neuroinflammation, Aβ production and brain insulin resistance. At the brain level Aβ oligomers trigger peripheral systemic glucose intolerance and insulin resistance in rodents, through a process of hypothalamic neuroinflammation (Clarke et al., 2015, 2018; Lourenco et al., 2019). Likewise, cerebral Aβ could traverse the blood-brain barrier (BBB) and affect peripheral tissues, leading to a peripheral insulin resistance. This mechanism would behave in a positive feedback loop that would worsen over time. cognition (Banks et al., 2018). These results confirm that IL-6 and TNFα in peripheral blood (Swardfager et al., 2010; modulation of peripheral metabolism, for example lowering Zheng et al., 2018). elevated levels of triglycerides in the blood, could be a strategy Regarding the possibility that peripheral chronic to treat obesity and cognitive impairment associated with CNS inflammation can contribute to cognitive decline and cause resistance to leptin and insulin. In another interesting study, LOAD, data show that IR tyrosine kinases trigger the activation Moreno-Gonzalez et al. (2017) demonstrated that IAPP (amylin) of the RAS/MAPKs pathway. This superfamily includes aggregates are able to enhance the aggregation of Aβ, providing a extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2), potential additional link between AD and T2DM. Clearly, future p38 and c-JNKs (Coffey, 2014). Moreover, it has been reported studies will provide further keys to understand the relation that ERK1 and ERK2 play a very significant role in the control between cognitive loss, obesity and T2DM (Vazquez-Valls et al., of synapses in the learning and memory processes, while the 2011; Mukherjee et al., 2017). contribution of p38 in associative learning has been described marginally (Sherrin et al., 2010, 2011). Likewise, CREB is ROLE OF JNK1 AS A TARGET FOR the main target of ERK and has a pivotal role in long-term DIABETES TYPE 2 AND OBESITY memory and synaptic plasticity in the hippocampus (Suzuki et al., 2011; Teich et al., 2015). Regarding to JNK family, it Obesity triggers inflammatory processes that spread through the consists of three members, JNK1 (Mapk8), JNK2 (Mapk9) and human body affecting multiple organs and tissues. Consequently, JNK3 (Mapk10; Sabio and Davis, 2010; Auladell et al., 2017; brains of HFD-exposed mice showed neuroinflammation and Solinas and Becattini, 2017). It has been proposed that the glial responses (Busquets et al., 2017). In a very recent review JNKs are involved in memory formation during learning under on this topic, authors described how HFD, western diet or stressful conditions through the regulation of their activity sugars cause obesity-derived neuroinflammation, affecting brain (Coffey, 2014). Short-term activation of JNKs will temporarily structures such as the hippocampus, hypothalamus, cortex, boost memory performance, whereas prolonged activation of brainstem, or amygdala (Guillemot-Legris et al., 2016). Similarly, JNKs may be a contributing factor to memory deficit and even AD patients exhibit significantly higher concentrations of neurodegeneration (Sherrin et al., 2011). The pro-inflammatory Frontiers in Aging Neuroscience | www.frontiersin.org 7 September 2019 | Volume 11 | Article 236 Folch et al. Brain Insulin Resistance in Alzheimer’s cytokine TNF-α activates JNK1 (Sabio and Davis, 2010; Solinas et al., 2015). Likewise, recent studies suggest that activated and Becattini, 2017). Indeed, it has been shown that JNKs are protein RNA kinase, also known as protein kinase R (PKR), activated in obese humans, thus, JNK1 could be implicated in plays an important role in insulin resistance induced by a HFD the mechanism of obesity-induced insulin resistance (Belgardt diet (Taga et al., 2018). Based on this activation sequence, et al., 2010). Therefore, the characterization of JNK isoforms JNK1 modulation looks like a promising molecule for future in the hippocampus and their role in memory processes seems development of novel therapeutic targets aiming to prevent paramount to understand the links among obesity, T2DM and T2DM. Consequently, selective inhibitors like Licochalcone A, LOAD (Solinas and Becattini, 2017). may be suitable approaches to treat T2DM-related cognitive loss In the hippocampus, JNKs have both presynaptic and (Busquets et al., 2018). postsynaptic localizations and can regulate proteins from Unfortunately, there is a lack of natural or synthetic molecules synaptic vesicles, such as synaptotagmin-4 (Sherrin et al., 2010; capable to modulate the activity of JNKs so far. Among the Nisticò et al., 2015). JNKs also regulate second messenger extensive effort in exploring therapeutic interventions focusing systems such as cytosolic phospholipase A, cytoskeletal elements on JNK activity, the compound SP600125, a JNK inhibitor, (i.e., MAP2, TAU), nuclear hormone receptors (such as the has been the best characterized (Gao et al., 2017). However, glucocorticoid receptor) or transcription factors, including the application of SP600125 is very limited due to its low c-Jun (a member of the activator protein-1, AP-1), activator target selectivity, and its clinical efficacy is restricted due to its transcription factor (ATF)-2, CREB (calcium/cAMP) and Elk-1 poor aqueous solubility (Gao et al., 2017). Notwithstanding, (Sabio and Davis, 2010; Kant et al., 2013). Hence, all these selective, water-soluble and brain-penetrant JNK inhibitors substrates are potential JNKs targets during the learning process. have been recently tested (Kumar et al., 2016). I.P. and i.c.v. Moreover, as previously mentioned, JNKs may be central administrations of SR11935, SR3306 and JNK2/3 isoform- mediators of many of the deleterious consequences of obesity, selective inhibitors indicated possible anorectic effects such as impaired glucose metabolism and insulin resistance (Ryu et al., 2016). (Belgardt et al., 2010). This hypothesis was proposed after exposing JNK1 knockout mice to an HFD. Surprisingly, these animals were protected from the development of impaired THE COMPLEX TREATMENT OF LATE glucose tolerance and insulin resistance (Pal et al., 2016). ONSET ALZHEIMER’S DISEASE: MORE Indeed, activated JNK1 phosphorylates the insulin receptor THAN ANTIDIABETIC DRUGS substrate 1 (IRS-1) in the serine residues (IRS-1pSer), blocking the insulin pathway and causing a peripheral resistance to At least, a link between cognitive loss and T2DM involves this hormone (Solinas and Becattini, 2017). Phosphorylation dysregulation of CNS circuits that control hepatic glucose in S307 is a mechanism by which the activation of JNK can production. Thus, targeting these circuits could be a novel directly antagonize insulin action. Therefore, phosphorylation potential strategy for the development of more effective of IRS1 following the activation of JNK1 has a key role in the therapies resulting in both, improved glucose regulation and insulin resistance mechanism and obesity process in mammals. cognitive performance. In this regard, our research group Likewise, the diabetic status alters the signaling pathway has already discussed the potential cognitive benefits from downstream of IR. Among others, it is relevant the energy drugs originally addressed to treat T2DM (Batista et al., alteration sensing pathway comprising the AMP-activated 2019; Forny-Germano et al., 2019). Indeed, some molecules protein kinase (AMPK)/sirtuin (SIRT)/peroxisome proliferator- used for the treatment of T2DM have shown neuroprotective activated receptor-γ coactivator α (PGC-1α; Fernyhough, 2015). effects in preclinical models of AD. These drugs included In fact, the intracellular ATP/ADP balance is regulated by intranasal insulin, sulfonylureas, PPARγ agonists, metformin AMPK, which acts as a master sensor that, in turns, also control and GLP-1 receptor agonists such as exendin-4, liraglutide the glucose and fatty acids consumption, and the mitochondrial and lixisenatide (de la Monte, 2017; Cummings et al., 2018; biogenesis through PGC-1α activity. The energy balance inside Batista et al., 2019). This opens a promising perspective for the hippocampal neurons allows for the formation, maintenance these antidiabetic drugs. For instance, new formulations of and reorganization of synapses, all of them critical processes dual GLP-1/GIP, and the triple combination GLP-1/GCG/GIP for brain development and appropriate responses generation agonists, which are the most effective drugs for weight loss, from neuronal circuits to environmental challenges (Cheng have been evaluated to treat LOAD (Camins et al., 2019). et al., 2012). These authors demonstrated how PGC-1α Likewise, the pharmacological combination of GLP-1/GCG/GIP activity increases dendritic spines and enhances the molecular has been shown to prevent the decline of brain glucose differentiation of synapses in cultured hippocampal cells metabolism in animal models (Capozzi et al., 2018). Molecularly, (Figure 2). Then, in light of evidences, it could be hypothesized the triagonist upregulated the expression of CREB, reverted PGC-1α as a molecular link between metabolic alterations cognitive impairment and enhanced Long-term potentiation involving brain diabetic status and cognitive impairment. (LTP) in preclinical models of AD (Tai et al., 2018). The In addition, other kinases such as nuclear kappa-β kinase activation of CREB by phosphorylation at Ser133 (S133p-CREB) inhibitor (IKK) play a crucial role in the development of is a critical step for memory formation and LTP maintenance insulin resistance associated with obesity, in both peripheral since the downstream genes are involved in synaptic formation, and CNS (Sabio and Davis, 2010; Kant et al., 2013; Nisticò neuronal plasticity and neurogenesis (Ettcheto et al., 2018a). Frontiers in Aging Neuroscience | www.frontiersin.org 8 September 2019 | Volume 11 | Article 236 Folch et al. Brain Insulin Resistance in Alzheimer’s FIGURE 2 | A suitable diet with natural products, for example rich in omega 3, antioxidants et cetera. can be a non-pharmacological complement for the prevention of obesity. Therefore, it would also have effects on the decrease of peripheral and central inflammatory processes. This mechanism would have effects on the prevention of central insulin resistance and improvement of the cognitive processes. The adherence over time to MedDiet would reduce the inflammatory levels in brain, with a decrease in the generation of mitochondrial stress and JUN N-terminal Kinases-1 (JNK-1) activation. It would allow insulin receptor pathway to fine tune the mitochondrial biogenesis according to the ATP/ADP intracellular balance of neuronal cells related to synaptogenesis and neuronal plasticity. However, taking into account the multidisciplinary nature of will include 3,500 subjects. However, Takeda Pharmaceutical AD, more than one drug should be administered to reach a Company Limited after a preliminary analysis of the results complete treatment capable of slowing the neurodegenerative reported that pioglitazone seems that was not effective in process. Therefore, a combination of drugs that acts on MCI-AD prevention. different pathways involved in the neuropathology of the The studies evaluating the administration of nasal insulin in disease (i.e., amyloidogenic pathway, metabolism disorders, the fight against forgetting (SNIFF) consists of a multicenter, excitotoxicity or neuroinflammation) could be the optimal double-blind, placebo-controlled phase 2/3 trial sponsored by choice to treat AD. Furthermore, these drugs should be the Cooperative Study of AD (ClinicalTrials.gov Identifier: administered as soon as possible to delay the process of NCT01767909). The study aims to evaluate the efficacy of cognitive loss. intranasal administered insulin on cognition, entorhinal cortex The antidiabetic drug pioglitazone has been evaluated for and hippocampal atrophy, and cerebrospinal fluid (CSF) AD treatment in the so-called TOMMORROW clinical trial biomarkers in amnestic mild cognitive impairment (aMCI) or (ClinicalTrials.gov Identifier: NCT01931566). This phase III mild AD. Thus, it will study AD biomarker profile, gender, or study assess delay of onset of MCI-AD in cognitively normal APOE-ε4 allele carriage predict treatment response. According subjects between 65 and 83 years of age. The study has two to the hypothesis after 12 months of treatment with nasal insulin objectives: the first is a new genetic test to determine whether compared to placebo, subjects would improve performance participants are at risk of developing a mild cognitive impairment on a global measure of cognition, on a memory composite related to AD (MCI-AD) in the 5 years of study based on a and on daily function. The results of the study have not yet genetic biomarker composed of TOMM40 and APOE genotypes been published. and age used at the time of study incorporation. The second Finally, as we have previously stated, it has been reported objective is to evaluate the efficacy of pioglitazone to delay that Memantine improves the metabolic consequences produced the onset of MCI-AD in cognitively normal people who are at by HFD in the APP/PS1 mice model of familial AD (Ettcheto high risk of developing MCI-AD (Roses et al., 2014). The study et al., 2018b). These results demonstrate new possibilities into the Frontiers in Aging Neuroscience | www.frontiersin.org 9 September 2019 | Volume 11 | Article 236 Folch et al. Brain Insulin Resistance in Alzheimer’s role of Memantine not only in the occurrence of AD treatment, intake of red and processed meats and foods that contain high but also into its potential application in peripheral metabolic amounts of added sugars (Trichopoulou et al., 2003). Indeed, disorders where Aβ could play a role, as is the case of T2DM recent results from non-Mediterranean populations suggest that (Ahmed et al., 2017; Folch et al., 2018). higher MedDiet adherence is associated with higher global cognitive performance and brain structural integrity, as well as decreased risk of AD and vascular dementia (VaD; Karstens NON-PHARMACOLOGICAL STRATEGIES et al., 2019). In this line, the geographic location of our research TO ENHANCE COGNITIVE group allows us to describe our own experience from a closer PERFORMANCE: DIET INTERVENTIONS point of view, studying human populations naturally adhered to MedDiet due to cultural reasons. The PREDIMED (in Spanish: In 2018, the group of Dr. Marta di Carlo published new results PREvención con DIeta MEDiterránea) study is a huge project in which they discussed the beneficial effects of a natural dietary that has published more than 200 articles in indexed journals supplement (NDS) containing Curcuma longa, silymarin, guggul, during the last decade. The results from primary prevention trials chlorogenic acid and inulin (Nuzzo et al., 2018). They showed reported that long-term adherence to a MedDiet, supplemented that NDS exerts neuroprotective effects in HFD mice by reducing with either extra-virgin olive oil or nuts, reduced cardiovascular brain fat accumulation, oxidative stress and inflammation, as well disease (Hu et al., 2013). Also, other studies on the antioxidant as by improving brain insulin resistance (Nuzzo et al., 2018). effects of walnuts proved evidence on their effects (Bulló et al., Hence, it seems that dietary content can enhance or destabilize 2010). The results from the PREDIMED project rapidly spread the delicate machinery that allows neurons to survive, which through other metabolic aspects related to a MedDiet adherence. leads to the following question: could diet influence cognitive Of note, Salas-Salvadó et al. (2016) reviewed the role of MedDiet performance in human populations? on preventing T2DM and stated that the role of the MedDiet As it is common in science, the answer goes probably on the prevention and management of T2DM and metabolic beyond a simple ‘‘yes’’ or ‘‘no,’’ but diet is indeed an important syndrome proves true according to the data of the study. In modifiable lifestyle factor related to the development of many turn, metabolomic studies allowed to identify plasma compounds pathologies and, among them there is all the different subtypes of with potential to predict both insulin resistance and incident dementia (Gustafson et al., 2015). The studies leaded by Dr. Mia T2DM (Papandreou et al., 2019). This is relevant since, both Kivipelto were the first to show that beneficial midlife dietary in T2DM and LOAD, prevention could be a key factor, and changes are associated with a reduced dementia risk later in there is still a lack of clear molecular markers allowing to detect life (Sindi et al., 2018). Their results highlighted the importance at-risk candidates soon enough to reverse the damaging effects of of targeting dietary patterns, describing how the combination these diseases. of determined food may have synergistic effects, thus further Conclusively, a PREDIMED study examined the effect potentiating their benefits. A meta-analysis by Hill et al. (2018, of T2DM on cognitive performance, specifically executive 2019) also revealed an effect of diet on AD biomarkers. With function tasks, in a large cohort of 6,823 patients above 2,726 records, the review supported the notion that diet and 55 years of age (Mallorquí-Bagué et al., 2018). In this cross- nutrition display potential for non-pharmacological strategies sectional study, T2DM (including illness duration), higher to improve the prognosis and prevent AD (Hill et al., 2018). Body Mass Index and lower mood were linked to lower More recent investigations also showed the potential cerebral cognitive function in older individuals with conditions like benefits of diet interventions in human populations. For instance, overweight/obesity and metabolic syndrome. Of note, MedDiet results from the Finnish Geriatric Intervention Study to Prevent includes a moderate intake of red wine and extra virgin Cognitive Impairment and Disability (FINGER), which included olive oil, both of them rich in polyphenolic compounds, 1,260 participants at-risk of cognitive decline (60–77 years), such as resveratrol, oleuropein, hydroxytyrosol and their allowed to conclude that, in fact, dietary changes seem to derivatives, which have shown anti-inflammatory effects on play a key role in preventing cognitive loss (Lehtisalo et al., microglia on in vitro and in vivo studies (Hornedo-Ortega 2019). In this study, the ingestion of a balanced diet was et al., 2018). According to these observations, it can be associated with positive changes in executive function, especially hypothesized the adherence over time to MedDiet would in the intervention group, after a 2-years follow-up. Hence, reduce the inflammatory levels in brain and the generation of these new approaches would show effects in the long term mitochondrial stress together with JNK-1 activation. It would and would be effective if they were to be followed for a long- allow insulin receptor pathway to fine tune the mitochondrial term. Thus, becoming complementary and preventive in the biogenesis according to the ATP/ADP intracellular balance long run. of neuronal cells related to synaptogenesis and neuronal This leads us to the next question: is there any particular plasticity (Figure 2). By contrast, the exposure to high fat diet to adhere in order to prevent cognitive loss? In this regard, diets, enriched in saturated fatty acids, would promote a growing body of evidence associate the Mediterranean diet the glial activation and mitochondrial oxidative stress. All (MedDiet) to preservation of cognitive performance in human those stressing factors would activate JNK-1 resulting in an populations. MedDiet is characterized by a high intake of fruits, impairment of insulin receptor pathway, causing and imbalance vegetables, legumes, fish, whole grains, nuts, and olive oil, a in ATP/ADP levels and a failure to maintain the synaptic moderate consumption of dairy products and wine, and a low connections (Figure 3). This hypothesis would explain how Frontiers in Aging Neuroscience | www.frontiersin.org 10 September 2019 | Volume 11 | Article 236 Folch et al. Brain Insulin Resistance in Alzheimer’s FIGURE 3 | The exposure to high fat diets over time, enriched in saturated fatty acids, would promote the glial activation and an increased mitochondrial oxidative stress. All those stressing factors would activate JNK-1 resulting in an impairment of insulin receptor pathway, causing and imbalance in ATP/ADP levels and a failure to control mitochondrial biogenesis and to maintain the synaptic connexions. This hypothesis would explain how JNK-1 should be a key factor linking diet and insulin signaling to synaptogenesis failure. JNK-1 should be a key factor linking diet and insulin signaling on dysregulated circulating miRNAs in obesity and T2DM to synaptogenesis failure. do not match with those from AD patients. Despite these Interestingly, one of the latest reports from the PREDIMED negative preliminary observations, undoubtedly further studies project revealed changes in circulating MicroRNAs (miRNAs). on circulating miRNAs could open a new therapeutic perspective The GLYNDIET study is a 6-month, parallel, randomized clinical for patients affected by LOAD. trial conducted on overweight and obese subjects. Results from GLYNDIET recently showed that the intake of an energy- NEW PERSPECTIVES IN THE NEAR restricted low-glycaemic index diet down-regulates circulating FUTURE miRNA-361 more than an energy-restricted high-glycaemic index, regardless of the magnitude of the weight loss Giardina As it has been discussed in this review article, recent results et al., 2019). Furthermore, Dr. Inestrosa stated in a seminal from multiple studies have contributed to reinforce the proposed review that miRNAs may be a molecular link in the complex concept of T3D. In addition, from all the gathered data, it relationship between metabolic syndrome and AD (Codocedo is clear that targeting LOAD early stages, before widespread et al., 2016) and, a recent systematic review extracted all miRNAs neurodegeneration has occurred, is likely to produce the best found to be significantly deregulated in peripheral blood and clinical outcome. However, detection of individuals at this stage cross-referenced them against the miRNAs deregulated in the is still difficult. Consequently, new and reinforced efforts should brain at Braak Stage III (Swarbrick et al., 2019). This resulted in be made towards the discovery and description of biomarkers a group of 10 miRNAs; hsa-mir-107, hsa-mir-26b, hsa-mir-30e, that will allow for the early detection of pre-clinical candidates hsa-mir-34a, hsa-mir-485, hsa-mir200c, hsa-mir-210, hsa-mir- for T2DM and/or LOAD. Clearly, a huge effort will be necessary 146a, hsa-mir-34c, and hsa-mir-125b that could be potentially to overcome this molecular complexity just like in the new involved in the regulation of these mechanisms. The authors formulation of new and more effective treatments for LOAD. hypothesized that these molecular markers could be deregulated For now, it seems that the testing of more anti-T2DM drugs early in AD, nearly 20 years before the emergence of clinical with beneficial effects against cognitive impairment has a certain symptoms (Swarbrick et al., 2019). Yet, PREDIMED results promising future. Frontiers in Aging Neuroscience | www.frontiersin.org 11 September 2019 | Volume 11 | Article 236 Folch et al. Brain Insulin Resistance in Alzheimer’s AUTHOR CONTRIBUTIONS FUNDING All the co-authors of this research (JF, JO, ME, OB, ES-L, The Spanish Ministry of Science and Innovation SAF2017- ACano, TE-J, GC, CB-Z, MG, CA, MB and ACamins) 84283-R, PI2016/01, CB06/05/0024 (CIBERNED), the European have directly participated in the planning, execution of the Regional Development Funds supported this work. Research manuscript. All authors have read and approved the final team from UB and URV belongs to 2017SGR625 from version submitted. Generalitat de Catalunya. REFERENCES Busquets, O., Ettcheto, M., Verdaguer, E., Castro-Torres, R. D., Auladell, C., Beas-Zarate, C., et al. (2018). JNK1 inhibition by Licochalcone A leads Abbott, M. A., Wells, D. G., and Fallon, J. R. (1999). The insulin receptor to neuronal protection against excitotoxic insults derived of kainic tyrosine kinase substrate p58/53 and the insulin receptor are components acid. Neuropharmacology 131, 440–452. doi: 10.1016/j.neuropharm.2017. of CNS synapses. J. Neurosci. 19, 7300–7308. doi: 10.1523/jneurosci.19-17- 10.030 07300.1999 Cai, D. (2013). Neuroinflammation and neurodegeneration in overnutrition- Ahmed, A. S., Elgharabawy, R. M., and Al-Najjar, A. H. (2017). Ameliorating induced diseases. Trends Endocrinol. Metab. 24, 40–47. doi: 10.1016/j.tem.2012. effect of anti-Alzheimer’s drugs on the bidirectional association between type 11.003 2 diabetes mellitus and Alzheimer’s disease. Exp. Biol. Med. 242, 1335–1344. Camins, A., Ettcheto, M., Busquets, O., Manzine, P. R., Castro-Torres, R. D., doi: 10.1177/1535370217711440 Beas-Zarate, C., et al. (2019). Triple GLP-1/GIP/glucagon receptor agonists, a Alzheimer’s Association. (2016). 2016 Alzheimer’s disease facts and figures. potential novel treatment strategy in Alzheimer’s disease. Expert Opin. Investig. Alzheimers Dement. 12, 459–509. doi: 10.1016/j.jalz.2016.03.001 Drugs 28, 93–97. doi: 10.1080/13543784.2019.1552677 An, Y., Varma, V. R., Varma, S., Casanova, R., Dammer, E., Pletnikova, O., Capozzi, M. E., DiMarchi, R. D., Tschöp, M. H., Finan, B., and Campbell, J. E. et al. (2018). Evidence for brain glucose dysregulation in Alzheimer’s disease. (2018). Targeting the incretin/glucagon system with triagonists Alzheimers Dement. 14, 318–329. doi: 10.1016/j.jalz.2017.09.011 to treat diabetes. Endocr. Rev. 39, 719–738. doi: 10.1210/er.2018- Arrieta-Cruz, I., and Gutiérrez-Juárez, R. (2016). The role of insulin resistance and 00117 glucose metabolism dysregulation in the development of Alzheimer’s disease. Cardoso, S., Seiça, R., and Moreira, P. I. (2017). ‘‘Diabesity and brain energy Rev. Invest. Clin. 68, 53–58. metabolism: the case of Alzheimer’s disease,’’ in Obesity and Brain Function. Arrieta-Cruz, I., Knight, C. M., and Gutiérrez-Juárez, R. (2015). Acute exposure Advances in Neurobiology, eds L. Letra and R. Seiça (Cham: Springer), of the mediobasal hypothalamus to amyloid-β25–35 perturbs hepatic glucose 117–150. metabolism. J. Alzheimers Dis. 46, 843–848. doi: 10.3233/jad-131865 Castellani, R. J., Plascencia-Villa, G., and Perry, G. (2019). The amyloid cascade Auladell, C., de Lemos, L., Verdaguer, E., Ettcheto, M., Busquets, O., and Alzheimer’s disease therapeutics: theory versus observation. Lab. Invest. Lazarowski, A., et al. (2017). Role of JNK isoforms in the kainic acid 99, 958–970. doi: 10.1038/s41374-019-0231-z experimental model of epilepsy and neurodegeneration. Front. Biosci. 22, Chami, B., Steel, A. J., De La Monte, S. M., and Sutherland, G. T. (2016). The 795–814. doi: 10.2741/4517 rise and fall of insulin signaling in Alzheimer’s disease. Metab. Brain Dis. 31, Banks, W. A., Farr, S. A., Salameh, T. S., Niehoff, M. L., Rhea, E. M., Morley, J. E., 497–515. doi: 10.1007/s11011-016-9806-1 et al. (2018). Triglycerides cross the blood-brain barrier and induce central Cheke, L. G., Simons, J. S., and Clayton, N. S. (2016). Higher body mass index is leptin and insulin receptor resistance. Int. J. Obes. 42, 391–397. doi: 10.1038/ijo. associated with episodic memory deficits in young adults. Q. J. Exp. Psychol. 69, 2017.231 2305–2316. doi: 10.1080/17470218.2015.1099163 Batista, A. F., Bodart, V., De Felice, F. G., and Ferreira, S. T. (2019). Chen, Z., and Zhong, C. (2013). Decoding Alzheimer’s disease from perturbed Neuroprotective actions of glucagon-like peptide-1 (GLP-1) analogues cerebral glucose metabolism: implications for diagnostic and therapeutic in Alzheimer’s and Parkinson’s diseases. CNS Drugs 33, 209–223. strategies. Prog. Neurobiol. 108, 21–43. doi: 10.1016/j.pneurobio.2013. doi: 10.1007/s40263-018-0593-6 06.004 Belgardt, B. F., Mauer, J., and Brüning, J. C. (2010). Novel roles for JNK1 in Cheng, A., Wan, R., Yang, J. L., Kamimura, N., Son, T. G., Ouyang, X., et al. metabolism. Aging 2, 621–626. doi: 10.18632/aging.100192 (2012). Involvement of PGC-1α in the formation and maintenance of neuronal Biessels, G. J. (2013). Sweet memories: 20 years of progress in research on cognitive dendritic spines. Nat. Commun. 3:1250. doi: 10.1038/ncomms2238 functioning in diabetes. Eur. J. Pharmacol. 719, 153–160. doi: 10.1016/j.ejphar. Chua, L. M., Lim, M. L., Chong, P. R., Hu, Z. P., Cheung, N. S., and Wong, B. S. 2013.04.055 (2012). Impaired neuronal insulin signaling precedes Aβ42 accumulation in Bocarsly, M. E., Fasolino, M., Kane, G. A., LaMarca, E. A., Kirschen, G. W., female AβPPsw/PS1∆E9 mice. J. Alzheimers Dis. 29, 783–791. doi: 10.3233/jad- Karatsoreos, I. N., et al. (2015). Obesity diminishes synaptic markers, alters 2012-111880 microglial morphology, and impairs cognitive function. Proc. Natl. Acad. Sci. Clarke, J. R., Lyra E Silva, N. M., Figueiredo, C. P., Frozza, R. L., U S A 112, 15731–15736. doi: 10.1073/pnas.1511593112 Ledo, J. H., Beckman, D., et al. (2015). Alzheimer-associated Aβ oligomers Bru, J. C., Gautam, D., Burks, D. J., Gillette, J., Schubert, M., Orban, P. C., impact the central nervous system to induce peripheral metabolic et al. (2000). Role of brain insulin receptor in control of body weight deregulation. EMBO Mol. Med. 7, 190–210. doi: 10.15252/emmm.2014 and reproduction. Science 289, 2122–2125. doi: 10.1126/science.289. 04183 5487.2122 Clarke, J. R., Ribeiro, F. C., Frozza, R. L., De Felice, F. G., and Lourenco, M. V. Bu, X. L., Xiang, Y., Jin, W. S., Wang, J., Shen, L. L., Huang, Z. L., et al. (2018). (2018). Metabolic dysfunction in Alzheimer’s disease: from basic neurobiology Blood-derived amyloid-β protein induces Alzheimer’s disease pathologies. Mol. to clinical approaches. J. Alzheimers Dis. 64, S405–S426. doi: 10.3233/JAD- Psychiatry 23, 1948–1956. doi: 10.1038/mp.2017.204 179911 Bulló, M., Nogués, M. R., López-Uriarte, P., Salas-Salvadó, J., and Romeu, M. Cleary, J. P., Walsh, D. M., Hofmeister, J. J., Shankar, G. M., Kuskowski, M. A., (2010). Effect of whole walnuts and walnut-skin extracts on oxidant status in Selkoe, D. J., et al. (2005). Natural oligomers of the amyloid-β mice. Nutrition 26, 823–828. doi: 10.1016/j.nut.2009.09.002 protein specifically disrupt cognitive function. Nat. Neurosci. 8, 79–84. Busquets, O., Ettcheto, M., Pallàs, M., Beas-Zarate, C., Verdaguer, E., Auladell, C., doi: 10.1038/nn1372 et al. (2017). Long-term exposition to a high fat diet favors the appearance Codocedo, J. F., Ríos, J. A., Godoy, J. A., and Inestrosa, N. C. (2016). of β-amyloid depositions in the brain of C57BL/6J mice. A potential model Are microRNAs the molecular link between metabolic syndrome and of sporadic Alzheimer’s disease. Mech. Ageing Dev. 162, 38–45. doi: 10.1016/j. Alzheimer’s disease? Mol. Neurobiol. 53, 2320–2338. doi: 10.1007/s12035-015- mad.2016.11.002 9201-7 Frontiers in Aging Neuroscience | www.frontiersin.org 12 September 2019 | Volume 11 | Article 236 Folch et al. Brain Insulin Resistance in Alzheimer’s Coffey, E. T. (2014). Nuclear and cytosolic JNK signalling in neurons. Nat. Rev. Fernyhough, P. (2015). Mitochondrial dysfunction in diabetic neuropathy: a series Neurosci. 15, 285–299. doi: 10.1038/nrn3729 of unfortunate metabolic events. Curr. Diab. Rep. 15:89. doi: 10.1007/s11892- Correia, S. C., Santos, R. X., Perry, G., Zhu, X., Moreira, P. I., and 015-0671-9 Smith, M. A. (2011). Insulin-resistant brain state: the culprit in sporadic Ferreira, S. T., Clarke, J. R., Bomfim, T. R., and De Felice, F. G. (2014). Alzheimer’s disease? Ageing Res. Rev. 10, 264–273. doi: 10.1016/j.arr.2011. Inflammation, defective insulin signaling, and neuronal dysfunction in 01.001 Alzheimer’s disease. Alzheimers Dement. 10, S76–S83. doi: 10.1016/j.jalz.2013. Cummings, J., Lee, G., Ritter, A., and Zhong, K. (2018). Alzheimer’s disease drug 12.010 development pipeline: 2018. Alzheimers Dement. 4, 195–214. doi: 10.1016/j.trci. Folch, J., Busquets, O., Ettcheto, M., Sánchez-López, E., Castro-Torres, R. D., 2018.03.009 Verdaguer, E., et al. (2018). Memantine for the treatment of dementia: a De Felice, F. G., Lourenco, M. V., and Ferreira, S. T. (2014). How does brain insulin review on its current and future applications. J. Alzheimers Dis. 62, 1223–1240. resistance develop in Alzheimer’s disease? Alzheimers Dement. 10, S26–S32. doi: 10.3233/JAD-170672 doi: 10.1016/j.jalz.2013.12.004 Folch, J., Pedrós, I., Patraca, I., Martínez, N., Sureda, F., and Camins, A. De Felice, F. G., Vieira, M. N., Bomfim, T. R., Decker, H., Velasco, P. T., (2013). Metabolic basis of sporadic Alzeimer’s disease. Role of hormones Lambert, M. P., et al. (2009). Protection of synapses against Alzheimer’s-linked related to energy metabolism. Curr. Pharm. Des. 19, 6739–6748. toxins: insulin signaling prevents the pathogenic binding of Aβ oligomers. Proc. doi: 10.2174/13816128113199990612 Natl. Acad. Sci. U S A 106, 1971–1976. doi: 10.1073/pnas.0809158106 Forny-Germano, L., De Felice, F. G., and Vieira, M. N. D. N. (2019). de la Monte, M. S. (2012). Brain insulin resistance and deficiency as The role of leptin and adiponectin in obesity-associated cognitive decline therapeutic targets in Alzheimers disease. Curr. Alzheimer Res. 9, 35–66. and Alzheimer’s disease. Front. Neurosci. 12:1027. doi: 10.3389/fnins.2018. doi: 10.2174/156720512799015037 01027 de la Monte, S. M. (2014). Relationships between diabetes and cognitive Freiherr, J., Hallschmid, M., Frey, W. H. II., Brünner, Y. F., Chapman, C. D., impairment. Endocrinol. Metab. Clin. North Am. 43, 245–267. doi: 10.1016/j. Hölscher, C., et al. (2013). Intranasal insulin as a treatment for alzheimer’s ecl.2013.09.006 disease: a review of basic research and clinical evidence. CNS Drugs 27, de la Monte, S. M. (2017). Insulin resistance and neurodegeneration: progress 505–514. doi: 10.1007/s40263-013-0076-8 towards the development of new therapeutics for Alzheimer’s disease. Drugs Frölich, L., Müller, W. E., and Riederer, P. (2015). Editorial: siegfried Hoyer’s 77, 47–65. doi: 10.1007/s40265-016-0674-0 concept of Alzheimer pathophysiology. J. Neural Transm. 122, 495–497. de la Monte, S. M., Tong, M., Daiello, L. A., and Ott, B. R. (2019). Early- doi: 10.1007/s00702-015-1371-y stage Alzheimer’s disease is associated with simultaneous systemic and Gao, S., Howard, S., and Lograsso, P. V. (2017). Pharmacological inhibition of central nervous system dysregulation of insulin-linked metabolic pathways. c-Jun N-terminal kinase reduces food intake and sensitizes leptin’s anorectic J. Alzheimers Dis. 68, 657–668. doi: 10.3233/JAD-180906 signaling actions. Sci. Rep. 7:41795. doi: 10.1038/srep41795 de la Monte, S. M., Tong, M., Lester-Coll, N., Plater, M. Jr., and Wands, J. R. Gauthier, S., Albert, M., Fox, N., Goedert, M., Kivipelto, M., Mestre-Ferrandiz, J., (2006). Therapeutic rescue of neurodegeneration in experimental type et al. (2016). Why has therapy development for dementia failed in the 3 diabetes: relevance to Alzheimer’s disease. J. Alzheimers Dis. 10, 89–109. last two decades? Alzheimers Dement. 12, 60–64. doi: 10.1016/j.jalz.2015. doi: 10.3233/jad-2006-10113 12.003 de la Monte, S. M., Tong, M., and Wands, J. R. (2018). The 20-year Giardina, S., Hernández-Alonso, P., Díaz-López, A., Salas-Huetos, A., Salas- voyage aboard the journal of Alzheimer’s disease: docking at ‘type Salvadó, J., and Bulló, M. (2019). Changes in circulating miRNAs in healthy 3 diabetes’, environmental/exposure factors, pathogenic mechanisms, and overweight and obese subjects: effect of diet composition and weight loss. Clin. potential treatments. J. Alzheimers Dis. 62, 1381–1390. doi: 10.3233/JAD- Nutr. 38, 438–443. doi: 10.1016/j.clnu.2017.11.014 170829 Gonçalves, R. A., Wijesekara, N., Fraser, P. E., and De Felice, F. G. (2019). The de la Monte, S. M., and Wands, J. R. (2008). Alzheimer’s disease is link between tau and insulin signaling: implications for Alzheimer’s disease type 3 diabetes-evidence reviewed. J. Diabetes Sci. Technol. 2, 1101–1113. and other tauopathies. Front. Cell. Neurosci. 13:17. doi: 10.3389/fncel.2019. doi: 10.1177/193229680800200619 00017 Deng, S.-N., Yan, Y.-H., Zhu, T.-L., Ma, B.-K., Fan, H.-R., Liu, Y.-M., et al. (2019). Grillo, C. A., Piroli, G. G., Lawrence, R. C., Wrighten, S. A., Green, A. J., Long-term NMDAR antagonism correlates weight loss with less eating. Front. Wilson, S. P., et al. (2015). Hippocampal insulin resistance impairs spatial Psychiatry 10:15. doi: 10.3389/fpsyt.2019.00015 learning and synaptic plasticity. Diabetes 64, 3927–3936. doi: 10.2337/ Dobson, C. M. (2017). The amyloid phenomenon and its links with human disease. db15-0596 Cold Spring Harb. Perspect. Biol. 9:a023648. doi: 10.1101/cshperspect.a023648 Guillemot-Legris, O., Masquelier, J., Everard, A., Cani, P. D., Alhouayek, M., El Khoury, N. B., Gratuze, M., Papon, M.-A., Bretteville, A., and Planel, E. and Muccioli, G. G. (2016). High-fat diet feeding differentially affects (2014). Insulin dysfunction and Tau pathology. Front. Cell. Neurosci. 8:22. the development of inflammation in the central nervous system. doi: 10.3389/fncel.2014.00022 J. Neuroinflammation 13:206. doi: 10.1186/s12974-016-0666-8 Ettcheto, M., Abad, S., Petrov, D., Pedrós, I., Busquets, O., Sánchez-López, E., Gustafson, D. R., Clare Morris, M., Scarmeas, N., Shah, R. C., Sijben, J., et al. (2018a). Early preclinical changes in hippocampal creb-binding protein Yaffe, K., et al. (2015). New perspectives on Alzheimer’s disease and nutrition. expression in a mouse model of familial Alzheimer’s disease. Mol. Neurobiol. J. Alzheimers Dis. 46, 1111–1127. doi: 10.3233/JAD-150084 55, 4885–4895. doi: 10.1007/s12035-017-0690-4 Hardy, J. (2009). The amyloid hypothesis for Alzheimer’s disease: a critical Ettcheto, M., Sánchez-López, E., Gómez-Mínguez, Y., Cabrera, H., Busquets, O., reappraisal. J. Neurochem. 110, 1129–1134. doi: 10.1111/j.1471-4159.2009. Beas-Zarate, C., et al. (2018b). Peripheral and central effects of memantine 06181.x in a mixed preclinical mice model of obesity and familial Alzheimer’s Hargrave, S. L., Jones, S., and Davidson, T. L. (2016). The outward spiral: a vicious disease. Mol. Neurobiol. 55, 7327–7339. doi: 10.1007/s12035-018- cycle model of obesity and cognitive dysfunction. Curr. Opin. Behav. Sci. 9, 0868-4 40–46. doi: 10.1016/j.cobeha.2015.12.001 Ettcheto, M., Petrov, D., Pedrós, I., Alva, N., Carbonell, T., Beas-Zarate, C., Hill, E., Clifton, P., Goodwill, A. M., Dennerstein, L., Campbell, S., and Szoeke, C. et al. (2016). Evaluation of neuropathological effects of a high-fat diet in a (2018). Dietary patterns and β-amyloid deposition in aging Australian women. presymptomatic Alzheimer’s disease stage in APP/PS1 mice. J. Alzheimers Dis. Alzheimers Dement. 4, 535–541. doi: 10.1016/j.trci.2018.09.007 54, 233–251. doi: 10.3233/JAD-160150 Hill, E., Goodwill, M. A., Gorelik, A., and Szoeke, C. (2019). Diet and biomarkers Fadel, J. R., and Reagan, L. P. (2016). Stop signs in hippocampal insulin of Alzheimer’s disease: a systematic review and meta-analysis. Neurobiol. Aging signaling: the role of insulin resistance in structural, functional and behavioral 76, 45–52. doi: 10.1016/j.neurobiolaging.2018.12.008 deficits. Curr. Opin. Behav. Sci. 9, 47–54. doi: 10.1016/j.cobeha.2015. Hokama, M., Oka, S., Leon, J., Ninomiya, T., Honda, H., Sasaki, K., et al. 12.004 (2014). Altered expression of diabetes-related genes in Alzheimer’s disease Fasshauer, M., and Blüher, M. (2015). Adipokines in health and disease. Trends brains: the Hisayama study. Cereb. Cortex 24, 2476–2488. doi: 10.1093/cercor/ Pharmacol. Sci. 36, 461–470. doi: 10.1016/j.tips.2015.04.014 bht101 Frontiers in Aging Neuroscience | www.frontiersin.org 13 September 2019 | Volume 11 | Article 236 Folch et al. Brain Insulin Resistance in Alzheimer’s Hornedo-Ortega, R., Cerezo, A. B., de Pablos, R. M., Krisa, S., Lourenco, M. V., Frozza, R. L., de Freitas, G. B., Zhang, H., Kincheski, G. C., Richard, T., García-Parrilla, M. C., et al. (2018). Phenolic compounds Ribeiro, F. C., et al. (2019). Exercise-linked FNDC5/irisin rescues synaptic characteristic of the mediterranean diet in mitigating microglia-mediated plasticity and memory defects in Alzheimer’s models. Nat. Med. 25, 165–175. neuroinflammation. Front. Cell. Neurosci. 12:373. doi: 10.3389/fncel.2018. doi: 10.1038/s41591-018-0275-4 00373 Luciano, R., Barraco, G. M., Muraca, M., Ottino, S., Spreghini, M. R., Hoyer, S. (2002a). The aging brain. Changes in the neuronal insulin/insulin Sforza, R. W., et al. (2015). Biomarkers of Alzheimer disease, insulin resistance, receptor signal transduction cascade trigger late-onset sporadic Alzheimer and obesity in childhood. Pediatrics 135, 1074–1081. doi: 10.1542/peds. disease (SAD). A mini-review. J. Neural Transm. 109, 991–1002. doi: 10.1007/ 2014-2391 s007020200082 Lyra E Silva, N. M., Gonçalves, R. A., Boehnke, S. E., Forny-Germano, L., Hoyer, S. (2002b). The brain insulin signal transduction system and sporadic (type Munoz, D. P., and De Felice, F. G. (2019). Understanding the link between II) Alzheimer disease: an update. J. Neural Transm. 109, 341–360. doi: 10. insulin resistance and Alzheimer’s disease: insights from animal models. Exp. 1007/s007020200028 Neurol. 316, 1–11. doi: 10.1016/j.expneurol.2019.03.016 Hoyer, S. (2004). Glucose metabolism and insulin receptor signal transduction in Ma, Q.-L., Yang, F., Rosario, E. R., Ubeda, O. J., Beech, W., Gant, D. J., Alzheimer disease. Eur. J. Pharmacol. 490, 115–125. doi: 10.1016/j.ejphar.2004. et al. (2009). β-amyloid oligomers induce phosphorylation of tau and 02.049 inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: Hu, E. A., Toledo, E., Diez-Espino, J., Estruch, R., Corella, D., Salas-Salvado, J., suppression by omega-3 fatty acids and curcumin. J. Neurosci. 29, 9078–9089. et al. (2013). Lifestyles and risk factors associated with adherence to the doi: 10.1523/JNEUROSCI.1071-09.2009 mediterranean diet: a baseline assessment of the PREDIMED trial. PLoS One Macauley, S. L., Stanley, M., Caesar, E., Yamada, S., Raichle, M., Perez, R., 8:e60166. doi: 10.1371/journal.pone.0060166 et al. (2015). Hyperglycemia modulates extracellular amyloid-β levels and Huang, N. Q., Jin, H., Zhou, S. Y., Shi, J. S., and Jin, F. (2017). TLR4 is a link neuronal activity in vivo. J. Clin. Invest. 125, 2463–2467. doi: 10.1172/jci between diabetes and Alzheimer’s disease. Behav. Brain Res. 316, 234–244. 79742 doi: 10.1016/j.bbr.2016.08.047 Mallorquí-Bagué, N., Lozano-madrid, M., Toledo, E., Corella, D., Salas-Salvadó, J., Hurtado-Puerto, A. M., Russo, C., and Fregni, F. (2018). Alzheimer’s disease. Cuenca-Royo, A., et al. (2018). Type 2 diabetes and cognitive impairment in an Neuromethods 138, 297–338. doi: 10.1007/978-1-4939-7880-9_9 older population with overweight or obesity and metabolic syndrome: baseline Kandimalla, R., Thirumala, V., and Reddy, P. H. (2017). Is Alzheimer’s disease a cross-sectional analysis of the PREDIMED-plus study. Sci. Rep. 8:16128. type 3 diabetes? A critical appraisal. Biochim. Biophys. Acta 1863, 1078–1089. doi: 10.1038/s41598-018-33843-8 doi: 10.1016/j.bbadis.2016.08.018 Marciniak, E., Leboucher, A., Caron, E., Ahmed, T., Tailleux, A., Dumont, J., Kang, S., Lee, Y. H., and Lee, J. E. (2017). Metabolism-centric overview et al. (2017). Tau deletion promotes brain insulin resistance. J. Exp. Med. 214, of the pathogenesis of Alzheimer’s disease. Yonsei Med. J. 58, 479–488. 2257–2269. doi: 10.1084/jem.20161731 doi: 10.3349/ymj.2017.58.3.479 Maurer, K., and Hoyer, S. (2006). Alois Alzheimer revisited: differences in Kant, S., Barrett, T., Vertii, A., Noh, Y. H., Jung, D. Y., Kim, J. K., et al. (2013). Role origin of the disease carrying his name. J. Neural Transm. 113, 1645–1658. of the mixed-lineage protein kinase pathway in the metabolic stress response to doi: 10.1007/s00702-006-0592-5 obesity. Cell Rep. 4, 681–688. doi: 10.1016/j.celrep.2013.07.019 Miklossy, J., Qing, H., Radenovic, A., Kis, A., Vileno, B., Làszló, F., et al. (2010). Karstens, A. J., Tussing-Humphreys, L., Zhan, L., Rajendran, N., Cohen, J., β amyloid and hyperphosphorylated tau deposits in the pancreas in type Dion, C., et al. (2019). Associations of the Mediterranean diet with cognitive 2 diabetes. Neurobiol. Aging 31, 1503–1515. doi: 10.1016/j.neurobiolaging.2008. and neuroimaging phenotypes of dementia in healthy older adults. Am. J. Clin. 08.019 Nutr. 109, 361–368. doi: 10.1093/ajcn/nqy275 Molofsky, A. V., Krenick, R., Ullian, E., Tsai, H., Deneen, B., Richardson, W. D., Katsouri, L., Lim, Y. M., Blondrath, K., Eleftheriadou, I., Lombardero, L., et al. (2012). Astrocytes and disease: a neurodevelopmental perspective. Genes Birch, A. M., et al. (2016). PPARγ-coactivator-1α gene transfer reduces Dev. 26, 891–907. doi: 10.1101/gad.188326.112 neuronal loss and amyloid-β generation by reducing β-secretase in an Moreno-Gonzalez, I., Edwards III, G., Shahnawaz, M., Salvadores, N., Soto, C., Alzheimer’s disease model. Proc. Natl. Acad. Sci. U S A 113, 12292–12297. and Diaz-Espinoza, R. (2017). Molecular interaction between type 2 diabetes doi: 10.1073/pnas.1606171113 and Alzheimer’s disease through cross-seeding of protein misfolding. Mol. Kivipelto, M., Mangialasche, F., and Ngandu, T. (2018). Lifestyle interventions Psychiatry 22, 1327–1334. doi: 10.1038/mp.2016.230 to prevent cognitive impairment, dementia and Alzheimer disease. Nat. Rev. Morgen, K., and Frölich, L. (2015). The metabolism hypothesis of Alzheimer’s Neurol. 14, 653–666. doi: 10.1038/s41582-018-0070-3 disease: from the concept of central insulin resistance and associated Kohjima, M., Sun, Y., and Chan, L. (2010). Increased food intake leads to consequences to insulin therapy. J. Neural Transm. 122, 499–504. obesity and insulin resistance in the Tg2576 Alzheimer’s disease mouse model. doi: 10.1007/s00702-015-1377-5 Endocrinology 151, 1532–1540. doi: 10.1210/en.2009-1196 Moser, V. A., and Pike, C. J. (2017). Obesity accelerates Alzheimer-related Kothari, V., Luo, Y., Tornabene, T., O’Neill, A. M., Greene, M. W., Geetha, T., et al. pathology in APOE4 but not APOE3 mice. eNeuro 4:ENEURO.0077-17.2017. (2017). High fat diet induces brain insulin resistance and cognitive impairment doi: 10.1523/eneuro.0077-17.2017 in mice. Biochim. Biophys. Acta Mol. Basis Dis. 1863, 499–508. doi: 10.1016/j. Mukherjee, A., Morales-Scheihing, D., Salvadores, N., Moreno-Gonzalez, I., bbadis.2016.10.006 Gonzalez, C., Taylor-Presse, K., et al. (2017). Induction of IAPP amyloid Kulas, J. A., Puig, K. L., and Combs, C. K. (2017). Amyloid precursor deposition and associated diabetic abnormalities by a prion-like mechanism. protein in pancreatic islets. J. Endocrinol. 235, 49–67. doi: 10.1530/joe- J. Exp. Med. 214, 2591–2610. doi: 10.1084/jem.20161134 17-0122 Nisticò, R., Florenzano, F., Mango, D., Ferraina, C., Grilli, M., Di Prisco, S., Kumar, V., Kumar, M., Beniwal, V., Gupta, G. K., Kumar, S., and Kataria, R. et al. (2015). Presynaptic c-Jun N-terminal Kinase 2 regulates NMDA (2016). Synthesis of some aroylhydrazones and 2,5-disubstituted-1,3,4- receptor-dependent glutamate release. Sci. Rep. 5:9035. doi: 10.1038/srep oxadiazoles as DNA photocleaving agents. Med. Chem. 6, 474–485. 09035 doi: 10.4172/2161-0444.1000386 Nuzzo, D., Amato, A., Picone, P., Terzo, S., Galizzi, G., Bonina, F. P., et al. Kuo, Y., Kokjohn, T. A., Watson, M. D., Woods, A. S., Cotter, R. J., Sue, L. I., et al. (2018). A natural dietary supplement with a combination of nutrients prevents (2000). Elevated aβ42 in skeletal muscle of Alzheimer disease patients suggests neurodegeneration induced by a high fat diet in mice. Nutrients 10:E1130. peripheral alterations of AβPP metabolism. Am. J. Pathol. 156, 797–805. doi: 10.3390/nu10091130 doi: 10.1016/S0002-9440(10)64947-4 Nuzzo, D., Picone, P., Baldassano, S., Caruana, L., Messina, E., Gammazza, A., Lehtisalo, J., Levälahti, E., Lindström, J., Hänninen, T., Paajanen, T., Peltonen, M., et al. (2015). Insulin resistance as common molecular denominator et al. (2019). Dietary changes and cognition over 2 years within a multidomain linking obesity to Alzheimer’s disease. Curr. Alzheimer Res. 12, 723–735. intervention trial—the finnish geriatric intervention study to prevent cognitive doi: 10.2174/1567205012666150710115506 impairment and disability (FINGER). Alzheimers Dement. 15, 410–417. Obici, S. (2009). Minireview: molecular targets for obesity therapy in the brain. doi: 10.1016/j.jalz.2018.10.001 Endocrinology 150, 2512–2517. doi: 10.1210/en.2009-0409 Frontiers in Aging Neuroscience | www.frontiersin.org 14 September 2019 | Volume 11 | Article 236 Folch et al. Brain Insulin Resistance in Alzheimer’s Obici, S., Zhang, B. B., Karkanias, G., and Rossetti, L. (2002). Hypothalamic Sabio, G., and Davis, R. J. (2010). CJun NH2-terminal kinase 1 (JNK1): Roles in insulin signaling is required for inhibition of glucose production. Nat. Med. metabolic regulation of insulin resistance. Trends Biochem. Sci. 35, 490–496. 8, 1376–1382. doi: 10.1038/nm798 doi: 10.1016/j.tibs.2010.04.004 Osborne, D. M., Fitzgerald, D. P., O’Leary, K. E., Anderson, B. M., Sah, S. K., Lee, C., Jang, J. H., and Park, G. H. (2017). Effect of high-fat diet on Lee, C. C., Tessier, P. M., et al. (2016). Intrahippocampal administration of a cognitive impairment in triple-transgenic mice model of Alzheimer’s disease. domain antibody that binds aggregated amyloid-β reverses cognitive deficits Biochem. Biophys. Res. Commun. 493, 731–736. doi: 10.1016/j.bbrc.2017. produced by diet-induced obesity. Biochim. Biophys. Acta 1860, 1291–1298. 08.122 doi: 10.1016/j.bbagen.2016.03.005 Salas-Salvadó, S. J., Guasch-Ferré, M., Lee, C. H., Estruch, R., Clish, C. B., and Ott, A., Stolk, R. P., van Harskamp, F., Pols, H. A., Hofman, A., and Breteler, M. M. Ros, E. (2016). Protective effects of the mediterranean diet on type 2 diabetes (1999). Diabetes mellitus and the risk of dementia: the Rotterdam study. and metabolic syndrome. J. Nutr. 146, 920S–927S. doi: 10.3945/jn.115. Neurology 53, 1937–1942. doi: 10.1212/wnl.53.9.1937 218487 Pal, M., Febbraio, M. A., and Lancaster, G. I. (2016). The roles of c-Jun NH2- Salkovic-Petrisic, M., Knezovic, A., Hoyer, S., and Riederer, P. (2013). What terminal kinases (JNKs) in obesity and insulin resistance. J. Physiol. 594, have we learned from the streptozotocin-induced animal model of sporadic 267–279. doi: 10.1113/jp271457 Alzheimer’s disease, about the therapeutic strategies in Alzheimer’s research. Papandreou, C., Bullo, M., Ruiz-Canela, M., Dennis, C., Deik, A., Wang, D., J. Neural Transm. 120, 233–252. doi: 10.1007/s00702-012-0877-9 et al. (2019). Plasma metabolites predict both insulin resistance and incident Salkovic-Petrisic, M., Osmanovic, J., Grünblatt, E., Riederer, P., and Hoyer, S. type 2 diabetes: a metabolomics approach within the Prevencion con Dieta (2009). Modeling sporadic Alzheimer’s disease: the insulin resistant brain Mediterranea (PREDIMED) study. Am. J. Clin. Nutr. 109, 626–634. doi: 10. state generates multiple long-term morphobiological abnormalities including 1093/ajcn/nqy262 hyperphosphorylated tau protein and amyloid-β. J. Alzheimers Dis. 18, Parrella, E., Maxim, T., Maialetti, F., Zhang, L., Wan, J., Wei, M., et al. (2013). 729–750. doi: 10.3233/JAD-2009-1184 Protein restriction cycles reduce IGF-1 and phosphorylated tau and improve Sallam, H. S., Tumurbaatar, B., Zhang, W. R., Tuvdendorj, D., Chandalia, M., behavioral performance in an Alzheimer’s disease mouse model. Aging Cell 12, Tempia, F., et al. (2015). Peripheral adipose tissue insulin resistance alters 257–268. doi: 10.1111/acel.12049 lipid composition and function of hippocampal synapses. J. Neurochem. 133, Peila, R., Rodriguez, B. L., and Launer, L. J. (2002). Type 2 diabetes, APOE gene, 125–133. doi: 10.1111/jnc.13043 and the risk for dementia and related pathologies. Diabetes 51, 1256–1262. Sandoval, D. A., Obici, S., and Seeley, R. J. (2009). Targeting the CNS to doi: 10.2337/diabetes.51.4.1256 treat type 2 diabetes. Nat. Rev. Drug Discov. 8, 386–398. doi: 10.1038/ Petrov, D., Pedrós, I., Artiach, G., Sureda, F. X., Barroso, E., Pallàs, M., et al. nrd2874 (2015). High-fat diet-induced deregulation of hippocampal insulin signaling Sato, N., and Morishita, R. (2013). Plasma Aβ: a possible missing link and mitochondrial homeostasis deficiences contribute to Alzheimer disease between alzheimer disease and diabetes. Diabetes 62, 1005–1006. doi: 10.2337/ pathology in rodents. Biochim. Biophys. Acta 1852, 1687–1699. doi: 10.1016/j. db12-1549 bbadis.2015.05.004 Schrijvers, E. M., Witteman, J. C., Sijbrands, E. J., Hofman, A., Koudstaal, P. J., Plucińska, K., Dekeryte, R., Koss, D., Shearer, K., Mody, N., Whitfield, P. D., et al. and Breteler, M. M. (2010). Insulin metabolism and the risk of Alzheimer (2016). Neuronal human BACE1 knockin induces systemic diabetes in mice. disease: the Rotterdam study. Neurology 75, 1982–1987. doi: 10.1212/WNL. Diabetologia 59, 1513–1523. doi: 10.1007/s00125-016-3960-1 0b013e3181ffe4f6 Pomytkin, I., Costa-Nunes, J. P., Kasatkin, V., Veniaminova, E., Demchenko, A., Selkoe, D. J., and Hardy, J. (2016). The amyloid hypothesis of Alzheimer’s disease Lyundup, A., et al. (2018). Insulin receptor in the brain: mechanisms of at 25 years. EMBO Mol. Med. 8, 595–608. doi: 10.15252/emmm.201606210 activation and the role in the CNS pathology and treatment. CNS Neurosci. Sheng, B., Wang, X., Su, B., Lee, H. G., Casadesus, G., Perry, G., et al. (2012). Ther. 24, 763–774. doi: 10.1111/cns.12866 Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction Pratchayasakul, W., Sa-nguanmoo, P., Sivasinprasasn, S., Pintana, H., in Alzheimer’s disease. J. Neurochem. 120, 419–429. doi: 10.1111/j.1471-4159. Tawinvisan, R., Sripetchwandee, J., et al. (2015). Obesity accelerates cognitive 2011.07581.x decline by aggravating mitochondrial dysfunction, insulin resistance and Sherrin, T., Black, T., and Todorovic, C. (2011). C-Jun N-terminal kinases in synaptic dysfunction under estrogen-deprived conditions. Horm. Behav. 72, memory and synaptic plasticity. Rev. Neurosci. 22, 403–410. doi: 10.1515/rns. 68–77. doi: 10.1016/j.yhbeh.2015.04.023 2011.032 Raji, C. A., Ho, A. J., Parikshak, N. N., Becker, J. T., Lopez, O. L., Kuller, L. H., et al. Sherrin, T., Blank, T., Hippel, C., Rayner, M., Davis, R. J., and Todorovic, C. (2010). Brain structure and obesity. Hum. Brain Mapp. 31, 353–364. doi: 10. (2010). Hippocampal c-Jun-N-terminal kinases serve as negative regulators of 1002/hbm.20870 associative learning. J. Neurosci. 30, 13348–13361. doi: 10.1523/jneurosci.3492- Ramalingam, M., and Kim, S. J. (2014). Mechanisms of action of brain 10.2010 insulin against neurodegenerative diseases. J. Neural Transm. 121, 611–626. Shinohara, M., and Sato, N. (2017). Bidirectional interactions between diabetes doi: 10.1007/s00702-013-1147-1 and Alzheimer’s disease. Neurochem. Int. 108, 296–302. doi: 10.1016/j.neuint. Ribe, E. M., and Lovestone, S. (2016). Insulin signalling in Alzheimer’s disease and 2017.04.020 diabetes: from epidemiology to molecular links. J. Intern. Med. 280, 430–442. Sindi, S., Kåreholt, I., Eskelinen, M., Hooshmand, B., Lehtisalo, J., Soininen, H., doi: 10.1111/joim.12534 et al. (2018). Healthy dietary changes in midlife are associated with reduced Rodriguez-Rodriguez, P., Sandebring-Matton, A., Merino-Serrais, P., dementia risk later in life. Nutrients 10:E1649. doi: 10.3390/nu10111649 Parrado-Fernandez, C., Rabano, A., Winblad, B., et al. (2017). Tau Singh-Manoux, A., Dugravot, A., Shipley, M., Brunner, E. J., Elbaz, A., Sabia, S., hyperphosphorylation induces oligomeric insulin accumulation and insulin et al. (2018). Obesity trajectories and risk of dementia: 28 years of follow-up resistance in neurons. Brain 140, 3269–3285. doi: 10.1093/brain/awx256 in the whitehall II study. Alzheimers Dement. 14, 178–186. doi: 10.1016/j.jalz. Roher, A. E., Esh, C. L., Kokjohn, T. A., Castaño, E. M., Van Vickle, G. D., 2017.06.2637 Kalback, W. M., et al. (2009). Amyloid β peptides in human plasma and tissues Solinas, G., and Becattini, B. (2017). JNK at the crossroad of obesity, insulin and their significance for Alzheimer’s disease. Alzheimers Dement. 5, 18–29. resistance and cell stress response. Mol. Metab. 6, 174–184. doi: 10.1016/j. doi: 10.1016/j.jalz.2008.10.004 molmet.2016.12.001 Roses, A. D., Saunders, A. M., Lutz, M. W., Zhang, N., Hariri, A. R., Asin, K. E., Stanley, M., Macauley, S. L., and Holtzman, D. M. (2016). Changes in insulin and et al. (2014). New applications of disease genetics and pharmacogenetics to insulin signaling in Alzheimer’s disease: cause or consequence? J. Exp. Med. drug development. Curr. Opin. Pharmacol. 14, 81–89. doi: 10.1016/j.coph.2013. 213, 1375–1385. doi: 10.1084/jem.20160493 12.002 Steen, E., Terry, B. M., Rivera, E. J., Cannon, J. L., Neely, T. R., Ryu, Y., Jin, L., Kee, H. J., Piao, Z. H., Cho, J. Y., Kim, G. R., et al. (2016). Gallic Tavares, R., et al. (2005). Impaired insulin and insulin-like growth acid prevents isoproterenol-induced cardiac hypertrophy and fibrosis through factor expression and signaling mechanisms in Alzheimer’s disease—is regulation of JNK2 signaling and Smad3 binding activity. Sci. Rep. 6:34790. this type 3 diabetes?. J. Alzheimers Dis. 7, 63–80. doi: 10.3233/jad- doi: 10.1038/srep34790 2005-7107 Frontiers in Aging Neuroscience | www.frontiersin.org 15 September 2019 | Volume 11 | Article 236 Folch et al. Brain Insulin Resistance in Alzheimer’s Suzuki, A., Fukushima, H., Mukawa, T., Toyoda, H., Wu, L.-J., Zhao, M.-G., et al. Warren, M. W., Hynan, L. S., Weiner, M. F., Doody, R., Rountree, S., Capriles, V., (2011). Upregulation of CREB-mediated transcription enhances both short- et al. (2012). Lipids and adipokines as risk factors for Alzheimer’s disease. and long-term memory. J. Neurosci. 31, 8786–8802. doi: 10.1523/jneurosci. J. Alzheimers Dis. 29, 151–157. doi: 10.3233/jad-2012-111385 3257-10.2011 Wijesekara, N., Ahrens, R., Sabale, M., Wu, L., Ha, K., Verdile, G., et al. (2017). Swarbrick, S., Wragg, N., Ghosh, S., and Stolzing, A. (2019). Systematic review of Amyloid-β and islet amyloid pathologies link Alzheimer’s disease and type miRNA as biomarkers in Alzheimer’s disease. Mol. Neurobiol. 56, 6156–6167. 2 diabetes in a transgenic model. FASEB J. 31, 5409–5418. doi: 10.1096/fj. doi: 10.1007/s12035-019-1500-y 201700431r Swardfager, W., Lanctt, K., Rothenburg, L., Wong, A., Cappell, J., and Willette, A. A., Modanlo, N., and Kapogiannis, D. (2015). Insulin resistance Herrmann, N. (2010). A meta-analysis of cytokines in Alzheimer’s disease. Biol. predicts medial temporal hypermetabolism in mild cognitive impairment Psychiatry 68, 930–941. doi: 10.1016/j.biopsych.2010.06.012 conversion to Alzheimer disease. Diabetes 64, 1933–1940. doi: 10.2337/ Taga, M., Mouton-Liger, F., Sadoune, M., Gourmaud, S., Norman, J., Tible, M., db14-1507 et al. (2018). PKR modulates abnormal brain signaling in experimental obesity. Xia, M., Cheng, X., Yi, R., Gao, D., and Xiong, J. (2016). The binding receptors of PLoS One 13:e0196983. doi: 10.1371/journal.pone.0196983 Aβ: an alternative therapeutic target for Alzheimer’s disease. Mol. Neurobiol. Tai, J., Liu, W., Li, Y., Li, L., and Hölscher, C. (2018). Neuroprotective effects of a 53, 455–471. doi: 10.1007/s12035-014-8994-0 triple GLP-1/GIP/glucagon receptor agonist in the APP/PS1 transgenic mouse Yarchoan, M., Toledo, J. B., Lee, E. B., Arvanitakis, Z., Kazi, H., Han, L. Y., model of Alzheimer’s disease. Brain Res. 1678, 64–74. doi: 10.1016/j.brainres. et al. (2014). Abnormal serine phosphorylation of insulin receptor 2017.10.012 substrate 1 is associated with tau pathology in Alzheimer’s disease and Talbot, K., Wang, H. Y., Kazi, H., Han, L. Y., Bakshi, K. P., Stucky, A., et al. tauopathies. Acta Neuropathol. 128, 679–689. doi: 10.1007/s00401-014- (2012). Demonstrated brain insulin resistance in Alzheimer’s disease patients 1328-5 is associated with IGF-1 resistance, IRS-1 dysregulation and cognitive decline. Yun, S. W., and Hoyer, S. (2000). Effects of low-level lead on glycolytic J. Clin. Invest. 122, 1316–1338. doi: 10.1172/jci59903 enzymes and pyruvate dehydrogenase of rat brain in vitro: relevance to Tarasoff-Conway, J. M., Carare, R. O., Osorio, R. S., Glodzik, L., Butler, T., sporadic Alzheimer’s disease? J. Neural Transm. 107, 355–368. doi: 10. Fieremans, E., et al. (2015). Clearance systems in the brain-implications for 1007/s007020050030 Alzheimer disease. Nat. Rev. Neurol. 11, 457–470. doi: 10.1038/nrneurol. Zhang, Y., Zhou, B., Deng, B., Zhang, F., Wu, J., Wang, Y., et al. (2013). Amyloid- 2015.119 β induces hepatic insulin resistance in vivo via JAK2. Diabetes 62, 1159–1166. Teich, A. F., Nicholls, R. E., Puzzo, D., Fiorito, J., Purgatorio, R., Fa’, M., et al. doi: 10.2337/db12-0670 (2015). Synaptic therapy in Alzheimer’s disease: a CREB-centric approach. Zhao, W.-Q., De Felice, F. G., Fernandez, S., Chen, H., Lambert, M. P., Quon, M. J., Neurotherapeutics 12, 29–41. doi: 10.1007/s13311-014-0327-5 et al. (2008). Amyloid β oligomers induce impairment of neuronal insulin Tong, M., Leão, R., Vimbela, G. V., Yalcin, E. B., Kay, J., Krotow, A., et al. (2017). receptors. FASEB J. 22, 246–260. doi: 10.1096/fj.06-7703com Altered temporal lobe white matter lipid ion profiles in an experimental model Zhao, N., Liu, C. C., Van Ingelgom, A. J., Martens, Y. A., Linares, C., Knight, J. A., of sporadic Alzheimer’s disease. Mol. Cell. Neurosci. 82, 23–34. doi: 10.1016/j. et al. (2017). Apolipoprotein E4 impairs neuronal insulin signaling by trapping mcn.2017.04.010 insulin receptor in the endosomes. Neuron 96, 115.e5–129.e5. doi: 10.1016/j. Trichopoulou, A., Costacou, T., Bamia, C., and Trichopoulos, D. (2003). neuron.2017.09.003 Adherence to a mediterranean diet and survival in a Greek population. N. Engl. Zheng, H., Zhou, Q., Du, Y., Li, C., Xu, P., Lin, L., et al. (2018). The hypothalamus J. Med. 348, 2599–2608. doi: 10.1056/nejmoa025039 as the primary brain region of metabolic abnormalities in APP/PS1 transgenic Vazquez-Valls, E., Flores-Soto, M. E., Chaparro-Huerta, V., Torres- mouse model of Alzheimer’s disease. Biochim. Biophys. Acta Mol. Basis Dis. Mendoza, B. M., Gudiño-Cabrera, G., Rivera-Cervantes, M. C., et al. (2011). 1864, 263–273. doi: 10.1016/j.bbadis.2017.10.028 HIF-1α expression in the hippocampus and peripheral macrophages after glutamate-induced excitotoxicity. J. Neuroimmunol. 238, 12–18. doi: 10.1016/j. Conflict of Interest Statement: The authors declare that the research was jneuroim.2011.06.001 conducted in the absence of any commercial or financial relationships that could Walker, J. M., and Harrison, F. E. (2015). Shared neuropathological characteristics be construed as a potential conflict of interest. of obesity, type 2 diabetes and Alzheimer’s disease: impacts on cognitive decline. Nutrients 7, 7332–7357. doi: 10.3390/nu7095341 Copyright © 2019 Folch, Olloquequi, Ettcheto, Busquets, Sánchez-López, Cano, Walsh, D. M., Klyubin, I., Shankar, G. M., Townsend, M., Fadeeva, J. V., Betts, V., Espinosa-Jiménez, García, Beas-Zarate, Casadesús, Bulló, Auladell and Camins. et al. (2005). The role of cell-derived oligomers of Aβ in Alzheimer’s disease This is an open-access article distributed under the terms of the Creative Commons and avenues for therapeutic intervention. Biochem. Soc. Trans. 33, 1087–1090. Attribution License (CC BY). The use, distribution or reproduction in other forums doi: 10.1042/BST20051087 is permitted, provided the original author(s) and the copyright owner(s) are credited Wang, J., Gu, B. J., Masters, C. L., and Wang, Y. J. (2017). A systemic view of and that the original publication in this journal is cited, in accordance with accepted Alzheimer disease—insights from amyloid-β metabolism beyond the brain. academic practice. No use, distribution or reproduction is permitted which does not Nat. Rev. Neurol. 13, 612–623. doi: 10.1038/nrneurol.2017.111 comply with these terms. Frontiers in Aging Neuroscience | www.frontiersin.org 16 September 2019 | Volume 11 | Article 236