d6bd97d028d52c149589da975ec49c8c  pmc_29382127.pdf
d789388a83d52d0e3f849462cf7a53fdbd3be35c  pmc_29382127.pdf

Title:          The Implication of the Brain Insulin Receptor in Late Onset Alzheimer’s Disease Dementia
Subject:        Alzheimer’s disease (AD) is progressive neurodegenerative disorder characterized by brain accumulation of the amyloid  peptide (A), which form senile plaques, neurofibrillary tangles (NFT) and, eventually, neurodegeneration and cognitive impairment. Interestingly, epidemiological studies have described a relationship between type 2 diabetes mellitus (T2DM) and this pathology, being one of the risk factors for the development of AD pathogenesis. Information as it is, it would point out that, impairment in insulin signalling and glucose metabolism, in central as well as peripheral systems, would be one of the reasons for the cognitive decline. Brain insulin resistance, also known as Type 3 diabetes, leads to the increase of A production and TAU phosphorylation, mitochondrial dysfunction, oxidative stress, protein misfolding, and cognitive impairment, which are all hallmarks of AD. Moreover, given the complexity of interlocking mechanisms found in late onset AD (LOAD) pathogenesis, more data is being obtained. Recent evidence showed that A42 generated in the brain would impact negatively on the hypothalamus, accelerating the “peripheral” symptomatology of AD. In this situation, A42 production would induce hypothalamic dysfunction that would favour peripheral hyperglycaemia due to down regulation of the liver insulin receptor. The objective of this review is to discuss the existing evidence supporting the concept that brain insulin resistance and altered glucose metabolism play an important role in pathogenesis of LOAD. Furthermore, we discuss AD treatment approaches targeting insulin signalling using anti-diabetic drugs and mTOR inhibitors.
Keywords:       Alzheimer’s; insulin resistance; amyloid; TAU; cognition; insulin receptor; type 2 diabetes
Author:         Jaume Folch, Miren Ettcheto, Oriol Busquets, Elena Sánchez-López, Rubén D. Castro-Torres, Ester Verdaguer, Patricia R. Manzine, Saghar Rabiei Poor, María Luisa García, Jordi Olloquequi, Carlos Beas-Zarate, Carme Auladell and Antoni Camins
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Jhove (Rel. 1.6, 2011-01-04)
 Date: 2019-02-14 17:29:11 CET
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