Platelet Activation and Amyloidosis in Neurodegenerative Disorders

Platelets, traditionally recognised for their role in haemostasis, have emerged as active participants in the aetiology and progression of neurodegenerative disorders through mechanisms that bridge vascular dysfunction, inflammation and amyloid deposition. Upon activation, platelets release a spectrum of bioactive molecules, including amyloid precursor protein (APP) and proteolytic enzymes that generate amyloid-β (Aβ) peptides. These peptides not only contribute to cerebral amyloid angiopathy but also interact with endothelial cells and glia to exacerbate blood–brain barrier breakdown and chronic neuroinflammation. Dysregulated platelet activation fosters microthrombotic events and promotes the adherence of platelets to vascular amyloid deposits, amplifying local oxidative stress and matrix degradation. Concurrently, altered platelet transcriptomes and proteomes in ageing and Alzheimer’s disease reveal upregulation of inflammatory pathways and disturbances in protein degradation systems, underscoring platelets’ systemic contribution to neuronal injury. As peripheral indicators of central pathology, platelets present both mechanistic insight into amyloidogenic cascades and potential biomarkers or therapeutic targets aimed at modulating vascular and inflammatory facets of neurodegeneration.

Research from Nature Portfolio

Recent studies have shown that platelets derived from Alzheimer’s disease models can instigate cerebrovascular damage in otherwise healthy brain tissue. When infused into organotypic brain slices, disease-model platelets localise to cortical vessels, release matrix metalloproteinases and Aβ, and penetrate the vessel wall, triggering microglial activation and focal inflammation. Inhibition of metalloproteinase activity abrogates vascular disruption, highlighting a key role for platelet-associated proteases in the progression of cerebral amyloid angiopathy. These findings elucidate a direct mechanism by which platelet-borne amyloidogenic factors and proteolytic enzymes drive vascular pathology in neurodegenerative disease.

Platelet Activation and Amyloidosis in Neurodegenerative Disorders publication trend

The graph below shows the total number of articles in platelet activation and amyloidosis in neurodegenerative disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Platelet activation: The process by which circulating platelets change shape, release granule contents and express adhesion molecules in response to vascular injury or inflammatory stimuli.

Amyloidosis: A group of conditions characterised by extracellular deposition of insoluble fibrillar proteins, notably amyloid-β in the brain and vessel walls.

Amyloid β (Aβ): Peptides generated by proteolytic cleavage of APP that aggregate into plaques and vascular deposits in Alzheimer’s disease.

Amyloid precursor protein (APP): A transmembrane protein abundantly expressed in neurons and platelets, whose cleavage yields amyloidogenic fragments.

Cerebral amyloid angiopathy (CAA): Deposition of amyloid proteins in the walls of cerebral blood vessels, contributing to vessel fragility and neurovascular dysfunction.

References

1. The platelet transcriptome and proteome in Alzheimer’s disease and aging: an exploratory cross-sectional study. Frontiers in Molecular Biosciences (2023).
2. Platelets isolated from an Alzheimer mouse damage healthy cortical vessels and cause inflammation in an organotypic ex vivo brain slice model. Scientific Reports (2018).
3. Role of amyloid peptides in vascular dysfunction and platelet dysregulation in Alzheimer’s disease. Frontiers in Cellular Neuroscience (2015).
4. Platelets, a reliable source for peripheral Alzheimer’s disease biomarkers?. Acta Neuropathologica Communications (2014).
5. Proteolytic Processing of Alzheimer's Disease βA4 Amyloid Precursor Protein in Human Platelets ∗. Journal of Biological Chemistry (1995).