Neurobiology of Disease 159 (2021) 105512 Contents lists available at ScienceDirect Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi Review Alternative platelet activation pathways and their role in neurodegenerative diseases Paula Ferrer-Raventós a, b, Katrin Beyer c, * a Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain b Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain c Department of Pathology, Germans Trias i Pujol Research Institute (IGTP), Universitat Autònoma de Barcelona (UAB), 08916 Badalona, Barcelona, Spain A R T I C L E I N F O A B S T R A C T Keywords: Purpose of the review: The study of platelets in the context of neurodegenerative diseases is intensifying, and Platelets increasing evidence suggests that platelets may play an important role in the pathogenesis of neurodegenerative Neurodegenerative diseases disorders. Therefore, we aim to provide a comprehensive overview of the role of platelets and their diverse Alternative platelet activation activation pathways in the development of these diseases. Alzheimer's disease Beta-amyloid Recent findings: Platelets participate in synaptic plasticity, learning, memory, and platelets activated by exercise Parkinson's disease promote neuronal differentiation in several brain regions. Platelets also contribute to the immune response by modulating their surface protein profile and releasing pro- and anti-inflammatory mediators. In Alzheimer's disease, increased levels of platelet amyloid precursor protein raise the production of amyloid-beta peptides promoting platelet activation, triggering at the same time amyloid-beta fibrillation. In Parkinson's disease, increased platelet α-synuclein is associated with elevated ROS production and mitochondrial dysfunction. Summary: In this review, we revise different platelet activation pathways, those classically involved in hemostasis and wound healing, and alternative activation pathways recently described in the context of neurodegenerative diseases, especially in Alzheimer's disease. 1. Introduction and neurons. Because of this accumulating evidence, it has been recently proposed that platelets might provide a link between environmental Platelets are small anucleated blood cells originally described as factors and brain homeostasis (Leiter and Walker, 2019). Taking into main actors in wound healing through different activation mechanisms. account these considerations, the present review aims to provide a However, over the past years, numerous additional physiological and comprehensive overview of the current knowledge on platelet activation pathological functions, including the mediation of synaptic plasticity mechanisms, their role in the pathogenesis of neurodegenerative dis­ and function, have been reported. Platelets are able to sense, adapt and orders and the contribution of APP/amyloid-beta and α-synuclein to respond, and, accordingly, their molecular composition varies depend­ disease-associated platelet dysfunction. ing on different environmental stimuli (Leiter and Walker, 2019). Therefore, platelets are attracting the interest of their study in the 2. Platelets and platelet activation context of different disorders. In both ageing and neurodegenerative diseases, reduced brain plasticity, as well as altered blood composition, Platelets have a biconvex discoid structure, a diameter of 2–3 μm and have been found; thus platelet dysfunction could be implicated in are formed by megakaryocytes in the bone marrow. After their release several neurodegenerative diseases and inflammatory CNS disorders into the blood stream, the normal count is of 150.000–350.000 platelets (Behari and Shrivastava, 2013). Platelets show an enzymatic pathway per μl, and their half-life ranges between 7 and 10 days (Paulus, 1975). similar to dopaminergic neurons, and can store and release neuro­ After sensing a stimulus, platelet reaction initiates and consequently the transmitters, such as serotonin, glutamate and dopamine. Oxidative activation process starts (Rendu and Brohard-Bohn, 2001). stress induces mitochondrial dysfunction and cell death in both platelets * Corresponding author. E-mail address: kbeyer@igtp.cat (K. Beyer). https://doi.org/10.1016/j.nbd.2021.105512 Received 29 June 2021; Received in revised form 8 September 2021; Accepted 14 September 2021 Available online 16 September 2021 0969-9961/© 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). P. Ferrer-Raventós and K. Beyer Neurobiology of Disease 159 (2021) 105512 2.1. Platelet activation pathways and aggregation diffusion of more platelet agonists consolidating the stability of the thrombus growth. In a situation of vessel wall injury and endothelial damage, platelet However, platelet activation can also be triggered by other molecules activation is directed to blood clot formation (Michelson, 2013). As (Tomaiuolo et al., 2017), such as serotonin, released from DGs (Coller, reviewed in detail by Rivera and colleagues (Rivera et al., 2009), the 1995; De Marco et al., 1985), collagen or epinephrine (Gremmel et al., process comprises the initiation phase, extension or amplification phase, 2016). Additional components are essential during later stages (for more which negative regulation prevents uncontrolled thrombus gout (Kaus­ detail see Estevez and Du, 2017), including aggregation (fibrinogen and kot and Hoylaerts, 2012), and the stabilization phase. In brief, in the vWF), perpetuation of the aggregation (receptors JAMA, JAMC, growth initiation phase several adhesion receptors on the platelet membrane arrest gene 6 and ephrin) and platelet-monocyte adhesion (e.g. P- surface interact directly or indirectly with collagen fibers (Knight et al., selectin) (Denis et al., 2005). Besides, these activation and aggregation 1999). At high shear rates, the binding of the Glycoprotein Ib-IX-V processes can be modulated by platelet antagonists, such as nitric oxide, complex to von Willebrand factor (VWF) is required (Nieuwenhuis prostacyclin and ADPase, produced by the vascular endothelium (Denis et al., 1986; Savage et al., 1998), permitting subsequent interaction et al., 2005; Offermanns et al., 1994). between glycoprotein VI receptor (GPVI) and integrin α2β1receptor Upon activation and response to different stimuli, platelets also (GPIa-IIa) to collagen (Savage et al., 1999). Simultaneously, several secrete two different microparticle populations (PMPs): (1) membrane integrins also bind to collagen, laminin, fibronectin, vironectin and/or budding microvesicles with similar content to the platelet plasma vWF (Kauskot and Hoylaerts, 2012). These processes initiate kinase membrane and inflammatory functions; (2) exosomes of endosomal activation and morphological platelet changes, leading to the extension origin, derived from AGs and multivesicular bodies (MVBs) with phase (Michelson, 2013; Rendu and Brohard-Bohn, 2001). Adherent numerous different functions (Coughlin, 2000; Offermanns et al., 1994). platelets then release the content of their granules: α-granules (AGs), δ-granules (DGs) and lysosomes (George, 2000). 2.2. RNAs in platelets The three main platelet activation pathways, summarized in Fig. 1, are mediated by: (1) ADP released from DGs, binding to P2Y1 and P2Y12 The above-discussed physiological changes during platelet activation (Murugappan and Kunapuli, 2006); (2) binding of TxA2, after conver­ are mediated by molecular pathways, which evolve rapidly, suggesting sion from arachidonic acid, to its receptor TP (Offermanns et al., 1994); that platelets are able to sustain de novo translation and post- (3) thrombin synthesis after exposure to tissue factor, and binding to transcriptional gene regulation (Gremmel et al., 2016). Although PARS (for more detail see Kauskot and Hoylaerts, 2012). Platelet platelets are anucleate lacking genomic DNA, they host diverse types of response to low concentrations of thrombin and TxA2 is reduced in the RNA. Evidence shows that platelet RNA is inherited from their parent absence of ADP, highlighting the key role of ADP as a positive feedback megakaryocytes (Denis et al., 2005), and a clear relationship between mediator and preserving platelet activation (Vaduganathan and Bhatt, the platelet transcriptome and proteome (McRedmond et al., 2004) 2016). underlies the ability of platelets to perform translational processes The final event of the cascade is the activation of the integrin (Booyse and Rafelson, 1967). Since the composition of platelet granules glycoprotein αIIbβ3 from a low affinity resting state through a confor­ varies depending on different environmental influences and factors, mational change to a high-affinity activated state (Coller, 1995). platelets are thought to collect mRNA also via endocytosis from the Consequently, the platelet receptor binds to extracellular soluble ligands plasma (Coppinger et al., 2007; Italiano et al., 2008). such as divalent plasma fibrinogen and monovalent vWF (De Marco In addition to precursor and mature RNA (pre-mRNA and mRNA) et al., 1985; Nieuwenhuis et al., 1986), acting as a bridge between involved in protein synthesis, other RNA families have been identified in platelets, creating the physical barrier stopping the blood loss. Platelets platelets. These include transfer and ribosomal RNA, and regulatory forming the plug have a very close contact, which decreases the RNAs as antisense and microRNA (miRNA) (Booyse and Rafelson, 1967; Fig. 1. Platelet adhesion and activation. Adherent platelets release the content of their granules. Three main platelet activation pathways have been characterized, and these are induced by ADP, TxA2 and thrombin. Created with biorender.com. 2 P. Ferrer-Raventós and K. Beyer Neurobiology of Disease 159 (2021) 105512 Thon and Devine, 2007). Indeed, platelets contain pre-mRNAs that can new platelet mechanisms have been found explaining that platelet be processed into mRNAs through splicing and levels of specific platelet concentration required for hemostasis is only 10 × 109 per litre (Duan miRNA correlate with platelet reactivity. Over the past decade, the et al., 2014; Fejes et al., 2017), which represents 2–6% of the total expression of functionally active miRNAs during platelet activation has platelet content in healthy individuals. These observations suggest that been described and investigated (Rowley et al., 2011; Schwertz et al., platelets have alternative functions beyond wound healing and ho­ 2006). meostasis of blood flow. Accordingly, alternative platelet activation MiRNAs and the corresponding functional miRNA pathway are pathways linking platelets to several biological processes have been common platelet constituents (Hunter et al., 2008; Landry et al., 2009). described. Eventually, shear and oxidative stress might alter platelet miRNAs play an important role during platelet genesis, activation and activation (Carnevale et al., 2014; Slichter, 2011), as well as hyperten­ human hematopoiesis (Hunter et al., 2008; Landry et al., 2009), and sion (Ehrlich et al., 2013; Violi and Pignatelli, 2012), physical activity play also an important role in the development of common diseases and the immune response, among others (Fig. 2). A study performed by (Dangwal and Thum, 2012; McManus and Freedman, 2015; Liang et al., Imhold and colleagues showed that immune stimulation results in 2015; Wojtukiewicz et al., 2017). Therefore, platelet miRNAs might platelet activation with an own proteomic signature, suggesting another represent potential biomarkers to predict disease and disease type of activation (Imhof et al., 2016). In fact, in an immune response progression. context, platelets increase surface molecules, up-regulating receptors and molecules to interact with other immune cells, as well as releasing 3. Platelets and brain homeostasis pro- and anti-inflammatory mediators (Clelland et al., 2009; Imhof et al., 2016) (Fig. 2). Additionally, platelets express several immune molecules 3.1. Alternative platelet activation and functions that may modulate brain function such as transforming growth factor-ß, ß-2 microglobulin, and gelsolin. Their translational machinery allows platelets to respond to a stim­ ulus by modifying their protein profile, experiencing morphological and 3.2. Platelets and brain functionality ultrastructural changes, highlighting their environmental adaptability. Platelets are considered a systemic tool, providing a link between In 2015, Heber and Volf reviewed the importance of acute exercise external factors and inner body homeostasis. During the last decades, and physical activity on platelets, stating that both modulate platelet Fig. 2. Platelet activation pathways. Wound-healing-dependent: The detection of a vascular breach leads to the release of the three main platelet activation factors: ADP, Thrombin and TxA2, resulting in clot formation. Wound-healing-independent: by physical activity – periods of acute physical activity lead to PF4 release and modification of the platelet transcriptome, and subsequently, to increasing proliferation of neural precursor cells (NPC) in the DG (hippocampal dentate gyrus); by immune response – platelets recognize direct immune-related receptors and ligands through conserved pattern recognition receptors or indirectly via leukocyte alarms, such as cytokines and/or neutrophil extracellular traps (NETs). Upon immune activation, platelet interactions with leukocytes are mediated by PSGL-1 and P- selectin, enabling pathogen phagocytosis. Physical interaction between platelets and leukocytes comprises signal exchange including arachidonic acid (AA) to synthesize TxA2, and allowing to generate a fully active inflammatory response. Created with biorender.com. 3 P. Ferrer-Raventós and K. Beyer Neurobiology of Disease 159 (2021) 105512 activation (Heber and Volf, 2015). In a recent study, Leiter and col­ Kasatkina and Borisova, 2013; Swerdlow et al., 2017). Their AGs contain leagues provided further evidence for the role of exercise on platelet bioactive neurogenesis promoting molecules, such as IGF1 and PF4, activation, reporting an elevated platelet activation rate in mice after 1 among others (Leiter and Walker, 2019), and express several neuronal day of acute running (Leiter et al., 2019). Platelets activated via exercise receptors (Wojsiat et al., 2017). Correspondingly, they seem to play a expressed a different protein profile suggesting the stimulation of a role in adult neurogenesis in the hippocampus (Leiter et al., 2019). different activation pathway. The study also showed that activated Finally, changes in platelet activation and aggregation have been platelets promote neuronal differentiation through platelet factor 4 documented in Lewy body diseases, amyotrophic lateral sclerosis (ALS) (PF4), resulting in a higher number of proliferating neural precursor and multiple sclerosis (MS) (Espinosa-Parrilla et al., 2019; Wojsiat et al., cells in the dentate gyrus and thus, contributing to the regulation of 2017). A common feature of these neurological diseases is the progres­ adult hippocampal neurogenesis (Fig. 2). Moreover, other studies indi­ sive loss of selective neuronal cell populations and the formation of cate that platelets also promote neurogenesis in the subventricular zone aggregates of misfolded proteins. The most common neurodegenerative (SVZ) (Leiter et al., 2019; Preston et al., 2003). Since the hippocampus is disorders are amyloidoses, α-synucleinopathies, tauopathies, and TDP- the most important region for learning and memory, and impairment in 43 proteinopathies, and platelets contain a high percentage of circu­ hippocampal neurogenesis results in cognitive decline, platelet activa­ lating amyloid precursor protein (APP) (Ponomarev, 2018; Rainesalo tion could be related to neurodegenerative diseases (Hayon et al., 2012; et al., 2005), and also α-synuclein (Barbour et al., 2008). Kazanis et al., 2015). Accordingly, these studies show a potential link between platelet activation and brain homeostasis. 4. Platelets in AD Additionally, during the last decade, the involvement of peripheral immune factors for the maintenance of brain function by different AD is characterized by the presence of neuritic plaques (NPs) and mechanisms has been described. First, immune cells participate in neurofibrillary tangles (NFTs) in the brain. Altered γ-secretase activity neuronal plasticity during development and adulthood (Morrell et al., leads to increased amyloid-beta (Aβ) peptide production after APP 2014; Von Hundelshausen and Weber, 2007). Second, a link between cleavage (Selkoe, 1994; Singh et al., 2016). Especially longer, more platelets and the complement system has been shown (Morimoto and hydrophobic peptides accumulate, shift the normal Aβ40/Aβ42 ratio, Nakajima, 2019; Nisticò et al., 2017), third, a recent study highlights the and enhance the generation of Aβ oligomers. Accumulation of these influence of acute peripheral immune activation to glial activation in rat oligomers gives rise to the formation of NPs, triggering tau hyper­ brains (Bruce et al., 2019), and fourth, alterations in the communication phosphorylation and the development of intraneuronal NFTs (Choi between immune and nervous systems result in pathological conditions, et al., 2014). including neurodegenerative diseases (Dantzer, 2018). 4.1. Effect of APP and Aβ on platelet activation 3.3. Implication of platelets in neurological processes Platelets contain about 90% of the circulating APP at their plasma Platelet counts are stable between the age of 20–60 years, but membrane and in AGs (Rendu and Brohard-Bohn, 2001), and host the decrease by approximately 10% in individuals older than 70 years complete enzymatic machinery to process the protein into Aβ peptides (Montenont et al., 2019). Women have around 15% more platelets than (Ponomarev, 2018; Rainesalo et al., 2005). Indeed, full-length APP, men, and this difference maintains with ageing. Although there is a encoded by platelet mRNA, acts as a platelet receptor, which upon decrease in the platelet number, the general increase in their reactivity activation shows a threefold increase at the platelet surface (Gardella correlating with increased plasma PF4 levels has been described (Mon­ et al., 1990). The effect of altered APP processing on platelets was tenont et al., 2019). Ageing also correlates with phenotypic and func­ described for the first time in 1997 (Abubaker et al., 2019), and in tional changes in monocytes, leading to increased platelet-monocyte several later studies, platelet alterations including increased β-secretase interactions resulting in an incremented inflammatory response (Hearps activity and altered APP metabolism have been observed. et al., 2012). The binding of activated platelets to monocytes activates a Moreover, there is extensive evidence showing that Aβ stimulates signaling cascade resulting in the synthesis of pro-inflammatory cyto­ platelet reaction (activation, adhesion and aggregation) (Sonkar et al., kines (Montenont et al., 2019). 2014), inducing changes in platelet structure and morphology, modifi­ Mitochondrial dysfunction is not only found in the CNS but in pe­ cations in the membrane fluidity (Grimm et al., 2006), increased release ripheral tissues such as skeletal muscle, liver and blood, in lymphocytes of ROS and altered APP processing (Ehrlich et al., 2013). The result is and platelets (Xu et al., 2007). Under pathological conditions and on abnormal platelet activation in a high ROS and neuroinflammatory physiological stimulation, platelets release reactive oxygen species environment, leading to mitochondrial dysfunction and apoptosis (ROS), leading to mitochondrial damage (Hearps et al., 2012; Xu et al., (Shrivastava et al., 2011b; Xu et al., 2007). 2007), specifically, to mitochondrial membrane depolarization, mem­ In this context, it was first shown that in vitro formed β-amyloid from brane permeability and alteration of the mitochondrial membrane po­ different proteins induces platelet activation through two pathways, tential (MMP) (Beal, 1996). In AD and other diseases, oxidative stress binding to the scavenger receptor CD36 and to GP1bα, and activating induces platelet and neuronal mitochondrial dysfunction and cell death p38 MAPK/COX1 pathways. These pathways induce the release of TxA2, (Barnham et al., 2004; Beal, 1996). Specifically, diminished respiratory triggering platelet activation (Herczenik et al., 2007). Later studies have parameters were found in platelet mitochondria of AD patients shown that both Aβ40 and Aβ42 bind GPIIb-IIIa, and initiate platelet compared with controls (Fišar et al., 2019). Also, the reduction of adhesion without degranulation, indicating that soluble Aβ peptides are mitochondrial enzymes, including pyruvate dehydrogenase complex, not able to fully activate platelets (Abubaker et al., 2019; Donner et al., enzymes of the citric acid cycle and respiratory complex IV was found in 2016). mitochondria from AD platelets, and these changes were comparable to Additionally, platelets from recently diagnosed AD patients present those characteristic for mitochondria from AD brain (Swerdlow et al., an increased activation state characterized by increased fibrinogen 2017). In this context it has been proposed that carnosine, a metal binding and altered morphology (Wiest et al., 2019). At the same time, chelator with heat-shock protein activation properties, might attenuate diminished aggregation response is characterized by decreased CD62P, ageing-induced ROS production (Banerjee and Poddar, 2020). Platelets and CD63 positivity indicating impaired platelet degranulation (Wiest also participate in synaptic plasticity, learning, memory and neuronal et al., 2019). However, a recent study in human platelet cultures differentiation (Bazan, 1998), and express an enzymatic pathway revealed that platelet activation after stimulation with soluble Aβ40 is similar to dopaminergic neurons, releasing neurotransmitters such as similar to activation after stimulation with collagen as measured by the serotonin, glutamate, and dopamine (Banasr et al., 2004; Bazan, 1998; release of ATP (Donner et al., 2020). This activation occurs through 4 P. Ferrer-Raventós and K. Beyer Neurobiology of Disease 159 (2021) 105512 Aβ40 binding and activation of both GPIIb-IIIa and GPVI receptor, decrease of α-secretase levels was accompanied by the age-dependent leading at the same time to the induction of Aβ fibril formation (Donner increase of β-secretase levels, mainly in SAMP8 mice. et al., 2020). Since the main substrate of platelet GPVI receptor are Another recent study was carried out in 14-months-old APP-PS1 collagen fibrils, fibrillary forms of Aβ may act as well as a substrate for transgenic mice presenting the full pathological spectrum (Knie­ GPVI (Abubaker et al., 2019), triggering a bi-directional loop with wallner et al., 2020). The most striking result revealed that 22% of increasing Aβ aggregation which at the same time increases platelet platelets were found in the extraluminal space of APP-PS1 mice brain activation (Fig. 3). Finally, recent studies suggested that Aβ42 has an compared with 6.8% in control mice. About 70% of these were activated even higher capacity of GPVI receptor binding (Abubaker et al., 2019), in APP-PS1 mice, but only a small percentage was in wild type mice. In and that both fibrillar Aβ40 and Aβ42 stimulate platelet aggregation contrast, no significant differences regarding the activation status were after activation of GPIb-IX-V and CD36 (Visconte et al., 2020). found in blood (Kniewallner et al., 2020). The question about how platelets may enter the brain was addressed in a very recent study, where platelets obtained from 15-months old APP-PS1 mice were 4.2. Relationship between platelet APP and Aβ and the brain injected into 10-month-old non-transgenic mice (Wu et al., 2021). As a result, not only the deposition of aggregated Aβ accompanied by the Several studies have investigated the effect of platelet APP and Aβ- activation of microglia was observed in the hippocampus, but increased peptides on the brain using different mouse models. One of these studies permeability of the blood-brain barrier (BBB) was also detected using an explored the relationship between Aβ levels in the hippocampus and in vitro BBB model (Wu et al., 2021). Once entered the brain, platelets platelets during normal and accelerated AD-like ageing (Chen et al., seem to contribute directly to blood vessel damage and might be able to 2019). Mice exhibiting fast ageing and accelerated senescence (SAMP8) modulate the function of specific cell types, enhancing disease devel­ were compared with similar mice but resistant to senescence (SAMR1). opment (Kniewallner et al., 2020). Mice were analyzed at 3, 6 and 9 months, and although Aβ40 and Aβ42 In addition to platelet heterogeneity caused by ultrastructural ab­ levels increased linearly with age in hippocampi and platelets of both normalities, AD platelets also show mitochondrial dysfunction, which SAMR1 and SAMP8 mice, Aβ levels were significantly higher in SAMP8 might be driven by COX deficiency (Linnebank et al., 2006; Selfridge mice. Especially in platelets of the oldest SAMP8 age group, both Aβ et al., 2013). Moreover, decreased glutamate uptake and glutamine peptides were drastically increased (Chen et al., 2019). Accordingly, Aβ synthetase dysfunction have also been described in platelets of various producing pathways were altered, and in platelets, an age-dependent Fig. 3. Effect of APP/Aβ and α-synuclein on platelets in AD and PD. In AD, elevated platelet APP levels increase Aβ production promoting platelet activation, raising reactive oxygen species (ROS) and altering APP processing. Abnormal platelet activation induces Aβ fibril formation and APP production, further enhancing platelet activation pathways. In PD, increased platelet α-synuclein triggers oxidative stress and mitochondrial dysfunction through complex I inhibition leading to increased ROS levels. MAO-B overexpression found in PD platelets causes, together with increased ROS, further inhibition of mitochondrial complex I resulting in mito­ chondrial dysfunction and altered platelet morphology. Created with biorender.com. 5 P. Ferrer-Raventós and K. Beyer Neurobiology of Disease 159 (2021) 105512 neurodegenerative diseases (Ferrarese et al., 2000). granule release by inhibiting Ca++-induced PF4 release (Park et al., 2002). The overexpression of platelet α-synuclein found in PD seems to 5. Platelets in synucleinopathies be associated with the promotion of oxidative stress leading to mito­ chondrial deficit (Fig. 3) (Hsu et al., 2000; Pei and Maitta, 2019) and Synucleinopathies include Lewy body diseases (LDB) and multiple induces changes in platelet morphology (Pei and Maitta, 2019). system atrophy (MSA), and are characterized by abnormal α-synuclein Accordingly, it has been reported, that platelets obtained from PD pa­ aggregation, primarily in the brain. Whereas in MSA α-synuclein ag­ tients have an increased volume compared to both AD patients and gregates in form of glial cytoplasmic inclusions, in LBD α-synuclein control individuals (Koçer et al., 2013). Finally, in contrast to Aβ, which aggregation leads to the formation of intraneuronal Lewy bodies and has been found in dense platelet microvesicle fractions, α-synuclein has Lewy neurites. LBD comprise dementia with Lewy bodies (DLB) and been detected in less dense microvesicles (Pienimaeki-Roemer et al., Parkinson's disease (PD), and platelets have been studied mainly in the 2015), underlining the involvement of both in different functions. context of the latter. 6. Platelets in other neurodegenerative diseases 5.1. Platelets in Parkinson's disease 6.1. Platelets in amyotrophic lateral sclerosis PD is the second most common neurodegenerative disorder after AD and currently, more than 10 million people are living with PD world­ ALS is a progressive neurodegenerative disorder that affects nerve wide (Dorsey et al., 2018). It develops after the loss of dopaminergic cells in the brain and the spinal cord. It presents a progressive decline of neurons in the substantia nigra, the ventral part of the pars compacta motor neuron functionality and subsequent respiratory failure and (SNpc), leading to motor symptoms including bradykinesia, tremor and death. This neuromuscular paralytic disorder has an incidence ranging rigidity (Jankovic, 2008). Although the molecular mechanisms under­ between 0.6 and 3.8/100000 person-years (Longinetti and Fang, 2019), lying the loss of these neurons remain unknown, the presence of Lewy and is highly devastating, with 50% of the cases dying in the first three bodies is detected early in the SNpc (Schapira and Jenner, 2011). As years of onset (Rowland and Shneider, 2001). Although ALS is still very most neurodegenerative diseases, PD is a multifactorial disorder, where poorly understood, it is known that in addition to the CSN, also pe­ the interaction of genetic and environmental factors is enhanced by the ripheral tissue is affected, playing a key role in ALS development (Bos ageing process (Riess and Krüger, 1999). et al., 2006; Kiernan et al., 2011). In PD, the link between peripheral tissue and CNS has been mainly However, during the last decades, several studies have reported described by mitochondrial dysfunction, which is one of the most abnormal properties of ALS platelets. Glutamate excitotoxicity is an affected pathways (Vos and Klein, 2021). Mitochondrial complex I important characteristic in ALS pathogenesis and could be explained by (NADH CoQ reductase) deficiency can explain neuronal apoptosis in the an atypical glutamine synthetase increase in platelets (Rao et al., 1992; SNpc accounting for one of the primary sources of ROS in PD. Early Smirnova and Festoff, 1994). The resulting decrease in glutamate uptake studies on mitochondrial function in PD revealed decreased complex I has also been reported for AD, PD and MS. Moreover, the increase of activity in different brain regions, fibroblasts, skeletal muscle, platelets, thrombospondin, a glycoprotein stored in AGs, is accompanied by se­ and complex II/III in lymphocytes and platelets (Blesa et al., 2015). The rotonin decrease in ALS platelets (Dupuis et al., 2010; Shrivastava et al., inhibition of mitochondrial complex I enhances the presence of ROS 2011a). These changes can be related to uncontrolled neuron excit­ species, which in turn inhibit complex I activity through negative ability. However, mitochondrial abnormalities and dysfunction are the feedback. Mitochondrial complex I is also inhibited by monoamine ox­ most important changes found in ALS platelets. In this context, Shriv­ idase B (MAO-B) (Lim et al., 2009), which is expressed in platelets and astava and colleagues identified changes in the permeability and po­ significantly increased in PD (Meredith et al., 2009). Thus, the high tential of the mitochondrial membrane, and ultrastructural platelet amount of ROS in PD platelets has been associated with altered platelet modifications in ALS cases (Briones et al., 2018; Dantzer, 2018). Ac­ activity in PD (Melchinger et al., 2019; Zhou et al., 2001) and points to cording to these results, Ehinger and colleagues demonstrated later that oxidative stress as a key factor for PD development (Fig. 3) (Lim et al., reduced complex IV activity was accompanied by an increase of mito­ 2009). However, if mitochondrial dysfunction found in platelets directly chondria in ALS blood cells (Ehinger et al., 2015). Recently, Marcelo enhances dopaminergic neurotoxicity in the SNpc remains to be et al. highlighted the importance of platelet–activating factor (PAF) as a elucidated. major mediator of neuroinflammation in platelets of a mice model for Moreover, glutamate levels are increased in the SNpc in PD, and ALS, proposing a potential novel therapy by using PAF-receptor specific impaired platelet glutamate uptake has been described in pathological inhibitors (Briones et al., 2018). conditions (Hashimoto et al., 1997; Pei and Maitta, 2019), and also dopamine uptake seems to be increased PD platelets (Roussakis et al., 6.2. Platelets in multiple sclerosis 2016). About 50% of patients develop PD with dementia (PDD) at later MS is a neurological disease that affects the CNS, including both the disease stages (Caballol et al., 2007). The brains of these patients are brain and spinal cord, and the peripheral nervous system. It is an characterized by an elevated burden of AD pathology, including accu­ immune-mediated demyelinating disorder in which the protective axon- mulation of Aβ in senile plaques, especially in cortical regions (Irwin and nerve-covering myelin sheath is damaged, leading to progressive et al., 2013; Jellinger, 2018). Since it is known that platelets are the sensation and motor deficits (Magyari and Sorensen, 2019; Spanevello primary source of systemic APP and Aβ, their involvement in PD pro­ et al., 2009). MS is considered the most common chronic inflammatory gression at later disease stages has been suggested (Inyushin et al., disease of the CNS, with a prevalence of more than 2.3 million people 2020). However, so far there are no studies addressing the role of worldwide (Magyari and Sorensen, 2019). platelet Aβ in the development of dementia in PD. Similar to the other neurodegenerative diseases, platelets in MS present abnormal activation, which seems to be associated with 5.2. The role of platelet α-synuclein in PD neuronal dysfunction. The myelin and axonal damage in MS is related to oxidative stress (Ohl et al., 2016; Spanevello et al., 2009), and platelets α-synuclein is expressed in platelets, participates in their differenti­ produce ROS affecting primarily glial cells, which change from resting to ation and localizes at the plasma membrane, the endoplasmatic reticu­ reactive state. Consequently, macrophages are activated and promote an lum, and the membrane of AGs (Hashimoto et al., 1997; Pei and Maitta, excessive attack on the myelin sheath, resulting in neuronal demyelin­ 2019). It participates in the regulation of vesicle transfer and platelet ation and tissue damage. Specifically, in MS, different cells have been 6 P. Ferrer-Raventós and K. Beyer Neurobiology of Disease 159 (2021) 105512 found in the brain corresponding to a previous infiltration through the development of AD-related pathology? BBB (Balashov et al., 1999). BBB damage is caused by activated platelets If, in fact, platelets directly contribute to disease development, which release mediators, increasing BBB permeability after being intervening in their activation triggering specific pathways might adhered to the endothelium (Imhof et al., 2016). The result is an in­ represent a novel therapeutic strategy for these diseases. crease in neurovascular inflammation (Dutta et al., 2006; Imhof et al., In summary, this review highlights the potential clinical significance 2016). of platelets as peripheral diagnostic and prognostic biomarkers for Also, mitochondrial dysfunction has been found in this pathology neurodegenerative diseases on the one hand, and as therapeutic targets, (Werner et al., 2000), and similar to ALS, the abnormal increase of on the other. Thus, as new potential biomarkers and technologies glutamine synthetase leads to less glutamate uptake, glutamate excito­ emerge, promising platelet-based testing and therapies might represent toxicity (Dutta et al., 2006), increased thrombospondin levels (Dutta a possible future direction for diagnosis and treatment of neurological et al., 2006), and the reduction of platelet serotonine (Hesse et al., disorders. 2014). Altogether, these changes have been associated with neuronal changes. Funding 7. Conclusions and future directions This study has been funded by Instituto de Salud Carlos III through the project “PI18/00276” (Co-funded by European Regional Development The aspects reviewed here show the complex mechanisms that un­ Fund/European Social Fund “A way to make Europe”/“Investing in your derlie platelet function. Several studies have demonstrated that platelet future”). function goes beyond hemostasis, thrombosis, and wound healing, and their role in numerous other biological mechanisms, including inflam­ Ethics approval mation, innate immunity and neurological processes has been described. Platelets regulate neural cells, contribute to brain plasticity and carry Not applicable. pro-neurogenic factors, and multiple mechanisms are involved platelet- neural cell communication. In this review, we discuss findings that link Consent to participate platelets to neurodegenerative diseases such as AD, PD, MS, and ALS. Neurodegenerative disorders are complex and heterogeneous, and Not applicable. the age-related development of overlapping brain pathologies difficults their clinical diagnosis. With the increasing age of the world population, Consent for publication the incidence of neurodegenerative diseases rises. On one hand, there is an urgent need to identify diagnostic and prognostic biomarkers to Not applicable. improve the clinical management of these patients, and on the other, therapeutic options are reduced and primarily comprise symptomatic Availability of data and material treatment. Accordingly, for AD, a disease affecting around 50 million people worldwide, the success rate of clinical trials is still below 1% Not applicable. (Cummings et al., 2014). This fact underlines the complexity of the development of assays for AD diagnosis and prognosis, and of effective Code availability therapies. Since the definitive diagnosis of most neurodegenerative diseases Not applicable. can only be achieved post-mortem, the use of peripheral biomarkers is mandatory. These can provide reliable, quick and safe data to be used for differential diagnosis. Currently, cerebrospinal fluid AD biomarkers are Declaration of Competing Interest available, but their obtaining through invasive interventions is a sig­ nificant disadvantage (Blennow et al., 2010).Therefore, blood compo­ Paula Ferrer-Raventós y Katrin Beyer have no conflict of interest. nents are being studied, and platelets were considered a systemic tool for investigating neurological disorders as early as the 1970s (Stahl, 1977). References Indeed, they are abundant in a small blood volume, easy to collect, and are able to change rapidly both their transcriptome and proteome in Abubaker, A.A., Vara, D., Visconte, C., Eggleston, I., Torti, M., Canobbio, I., Pula, G., response to different stimuli. We have discussed above that disease- Cascella, R., 2019. Amyloid peptide β1-42 induces integrin αIIbβ3 activation, platelet adhesion, and thrombus formation in a NADPH oxidase-dependent manner. specific conditions may modulate platelet activation, indicating that Oxidative Med. Cell. 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