The platelet transcriptome and proteome in Alzheimer's disease and aging: an exploratory cross-sectional study.

Introduction: Alzheimer's disease (AD) and aging are associated with platelet hyperactivity. However, the mechanisms underlying abnormal platelet function in AD and aging are yet poorly understood. Methods: To explore the molecular profile of AD and aged platelets, we investigated platelet activation (i.e., CD62P expression), proteome and transcriptome in AD patients, non-demented elderly, and young individuals as controls. Results: AD, aged and young individuals showed similar levels of platelet activation based on CD62P expression. However, AD and aged individuals had a proteomic signature suggestive of increased platelet activation compared with young controls. Transcriptomic profiling suggested the dysregulation of proteolytic machinery involved in regulating platelet function, particularly the ubiquitin-proteasome system in AD and autophagy in aging. The functional implication of these transcriptomic alterations remains unclear and requires further investigation. Discussion: Our data strengthen the evidence of enhanced platelet activation in aging and provide a first glimpse of the platelet transcriptomic changes occurring in AD.

Immune-mediated platelet depletion augments Alzheimer's disease neuropathological hallmarks in APP-PS1 mice.

In Alzheimer's disease (AD), platelets become dysfunctional and might contribute to amyloid beta deposition. Here, we depleted platelets in one-year-old APP Swedish PS1 dE9 (APP-PS1) transgenic mice for five days, using intraperitoneal injections of an anti-CD42b antibody, and assessed changes in cerebral amyloidosis, plaque-associated neuritic dystrophy and gliosis. In APP-PS1 female mice, platelet depletion shifted amyloid plaque size distribution towards bigger plaques and increased neuritic dystrophy in the hippocampus. In platelet-depleted females, plaque-associated Iba1+ microglia had lower amounts of fibrillar amyloid beta cargo and GFAP+ astrocytic processes showed a higher overlap with thioflavin S+ amyloid plaques. In contrast to the popular hypothesis that platelets foster plaque pathology, our data suggest that platelets might limit plaque growth and attenuate plaque-related neuritic dystrophy at advanced stages of amyloid plaque pathology in APP-PS1 female mice. Whether the changes in amyloid plaque pathology are due to a direct effect on amyloid beta deposition or are a consequence of altered glial function needs to be further elucidated.

TGF-ß Signaling: A Therapeutic Target to Reinstate Regenerative Plasticity in Vascular Dementia?

Vascular dementia (VaD) is the second leading form of memory loss after Alzheimer's disease (AD). Currently, there is no cure available. The etiology, pathophysiology and clinical manifestations of VaD are extremely heterogeneous, but the impaired cerebral blood flow (CBF) represents a common denominator of VaD. The latter might be the result of atherosclerosis, amyloid angiopathy, microbleeding and micro-strokes, together causing blood-brain barrier (BBB) dysfunction and vessel leakage, collectively originating from the consequence of hypertension, one of the main risk factors for VaD. At the histopathological level, VaD displays abnormal vascular remodeling, endothelial cell death, string vessel formation, pericyte responses, fibrosis, astrogliosis, sclerosis, microglia activation, neuroinflammation, demyelination, white matter lesions, deprivation of synapses and neuronal loss. The transforming growth factor (TGF) ß has been identified as one of the key molecular factors involved in the aforementioned various pathological aspects. Thus, targeting TGF-ß signaling in the brain might be a promising therapeutic strategy to mitigate vascular pathology and improve cognitive functions in patients with VaD. This review revisits the recent understanding of the role of TGF-ß in VaD and associated pathological hallmarks. It further explores the potential to modulate certain aspects of VaD pathology by targeting TGF-ß signaling.

Platelets in Amyloidogenic Mice Are Activated and Invade the Brain.

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.