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Published on: July 26, 2011
Increased platelet adhesion and thrombus formation in a mouse model of Alzheimer's disease
Ilaria Canobbio1, Caterina Visconte1, Barbara Oliviero2
1Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy.
Insights
Platelets in Alzheimer's disease models show increased adhesion and thrombus formation. These findings highlight platelet hyper-activation as a potential factor in Alzheimer's disease progression.
Area of Science:
- Neuroscience
- Hematology
- Cardiovascular Biology
Background:
- Alzheimer's disease (AD) and vascular dysfunctions share overlapping pathologies and risk factors.
- Cardiovascular risks like hypertension and diabetes elevate the likelihood of vascular dementia and AD.
- AD patients exhibit a higher predisposition to strokes, indicating a link between AD and cerebrovascular events.
Purpose of the Study:
- To investigate the morphology and function of platelets in a 3xTg-AD mouse model of Alzheimer's disease.
- To determine if Alzheimer's disease mutations affect platelet behavior in hemostasis and thrombosis.
Main Methods:
- Analysis of platelet number and glycoprotein expression in aged 3xTg-AD mice compared to wild-type controls.
- Assessment of platelet adhesion to various matrices (collagen, von Willebrand factor, fibrinogen, amyloid peptides) under static and shear conditions.
- Evaluation of signaling protein phosphorylation (Pyk2, Akt, p38MAPK, MLCK) in adherent platelets.
- Measurement of platelet aggregation and integrin αIIbβ3 activation in response to agonists.
Main Results:
- Platelets from aged 3xTg-AD mice maintained normal numbers and glycoprotein expression.
- 3xTg-AD platelets demonstrated enhanced adhesion to collagen, von Willebrand factor, fibrinogen, and amyloid peptides.
- Adherent 3xTg-AD platelets showed increased phosphorylation of key signaling proteins and improved thrombus formation under shear.
- Platelet aggregation and integrin αIIbβ3 activation were comparable between 3xTg-AD and wild-type mice.
Conclusions:
- Alzheimer's disease mutations induce a hyper-activated platelet state in a murine model.
- This platelet hyper-activation is associated with increased adhesion and thrombus formation capabilities.
- These findings suggest a significant role for platelet dysfunction in the progression of Alzheimer's disease.
Abstract:
Vascular dysfunctions and Alzheimer's disease show significant similarities and overlaps. Cardiovascular risk factors (hypercholesterolemia, hypertension, obesity, atherosclerosis and diabetes) increase the risk of vascular dementia and Alzheimer's disease. Conversely, Alzheimer's patients have considerably increased predisposition of ischemic and hemorrhagic strokes. Platelets are major players in haemostasis and thrombosis and are involved in inflammation. We have investigated morphology and function of platelets in 3xTg-AD animals, a consolidate murine model for Alzheimer's disease. Platelets from aged 3xTg-AD mice are normal in number and glycoprotein expression, but adhere more avidly on matrices such as fibrillar collagen, von Willebrand factor, fibrinogen and amyloid peptides compared to platelets from age-matching wild type mice. 3xTg-AD washed platelets adherent to collagen also show increased phosphorylation of selected signaling proteins, including tyrosine kinase Pyk2, PI3 kinase effector Akt, p38MAP kinase and myosin light chain kinase, and increased ability to form thrombi under shear. In contrast, aggregation and integrin αIIbβ3 activation induced by several agonists in 3xTg-AD mice are similar to wild type platelets. These results demonstrated that Alzheimer's mutations result in a significant hyper-activated state of circulating platelets, evident with the progression of the disease.
