Platelets in Amyloidogenic Mice Are Activated and Invade the Brain

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease with a complex and not fully understood pathogenesis. Besides brain-intrinsic hallmarks such as abnormal deposition of harmful proteins, i.e., amyloid beta in plaques and hyperphosphorylated Tau in neurofibrillary tangles, blood-derived elements, in particular, platelets have been discussed to be involved in AD pathogenesis. The underlying mechanisms, however, are rather unexplored. Here, we investigate a potential role of platelets in an AD transgenic animal model with severe amyloid plaque formation, the APP-PS1 transgenic mice, and analyzed the presence, spatial location and activation status of platelets within the brain. In APP-PS1 mice, a higher number of platelets were located within the brain parenchyma, i.e., outside the cerebral blood vessels compared to WT controls. Such platelets were activated according to the expression of the platelet activation marker CD62P and to morphological hallmarks such as membrane protrusions. In the brain, platelets were in close contact exclusively with astrocytes suggesting an interaction between these two cell types. In the bloodstream, although the percentage of activated platelets did not differ between transgenic and age-matched control animals, APP-PS1 blood-derived platelets showed remarkable ultrastructural peculiarities in platelet-specific organelles such as the open canalicular system (OCS). This work urges for further investigations on platelets and their yet unknown functional roles in the brain, which might go beyond AD pathogenesis and be relevant for various age-related neurodegenerative diseases.

Cross Brain–Gut Analysis Highlighted Hub Genes and LncRNA Networks Differentially Modified During Leucine Consumption and Endurance Exercise in Mice with Depression-Like Behaviors

“…On the other hand, platelet activation as the critical process has been associated with brain aging and neurodegenerative pathogenesis. The platelet activation process might trigger brain vascular abnormalities such as microvascular integrity disruption in depression conditions to preserve vascular integrity [ 52 ]. In a recent study, Ge Zhang and colleagues illustrated a disposition to platelet hyperactivity and micro-thrombosis risk in intestinal tissue in inflammatory bowel diseases, especially Crohn’s [ 32 ].…”

The Role of Platelets in the Stimulation of Neuronal Synaptic Plasticity, Electric Activity, and Oxidative Phosphorylation: Possibilities for New Therapy of Neurodegenerative Diseases

“…Very recent studies indicate that platelets can contribute to BBB disruption (Kopeikina et al, 2020 ; Wu et al, 2021 ) and can transfer Aβ from blood vessels into CNS (Wu et al, 2021 ; Table 1 ). Moreover, it was demonstrated that activated platelets from APP/PS1 transgenic mice invade brain parenchyma and are closely associated with astrocytes (Kniewallner et al, 2020 ) that are enriched with major brain gangliosides in lipid rafts of astroglial limitations and efficiently activate platelets (Sotnikov et al, 2013 ). Platelets and their secreted factors could affect many cell types involved in the regulation of BBB integrity including endothelial cells, astroglia, and pericytes (Fang et al, 2011 ; Gonzales et al, 2020 ; Kniewallner et al, 2020 ).…”

Is platelet activation a link between metabolic syndrome and cognitive impairment in patients with schizophrenia?

“…Platelets are also involved in neuroplasticity [14]. Importantly, activated platelets are capable of affecting the structural integrity of the BBB [29], penetrate and interact with the cellular components of the BBB matrix including astrocytes [30]. Relatedly, we found a positive correlation between plasma sP-selectin, and the astrocyte marker, S100B in patients with schizophrenia [17].…”