Abstract
Background: Alzheimer’s disease (AD) is characterized by an accumulation of amyloid β (Aβ) peptides in the brain and mitochondrial dysfunction. Platelet activation is enhanced in AD and platelets contribute to AD pathology by their ability to facilitate soluble Aβ to form Aβ aggregates. Thus, anti-platelet therapy reduces the formation of cerebral amyloid angiopathy in AD transgenic mice. Platelet mitochondrial dysfunction plays a regulatory role in thrombotic response, but its significance in AD is unknown and explored herein. Methods: The effects of Aβ-mediated mitochondrial dysfunction in platelets were investigated in vitro. Results: Aβ40 stimulation of human platelets led to elevated reactive oxygen species (ROS) and superoxide production, while reduced mitochondrial membrane potential and oxygen consumption rate. Enhanced mitochondrial dysfunction triggered platelet-mediated Aβ40 aggregate formation through GPVI-mediated ROS production, leading to enhanced integrin αIIbβ3 activation during synergistic stimulation from ADP and Aβ40. Aβ40 aggregate formation of human and murine (APP23) platelets were comparable to controls and could be reduced by the antioxidant vitamin C. Conclusions: Mitochondrial dysfunction contributes to platelet-mediated Aβ aggregate formation and might be a promising target to limit platelet activation exaggerated pathological manifestations in AD.
Highlights
In our previous studies we showed that aged mice from the Alzheimer’s disease (AD) transgenic mouse line APP23, which develop amyloid-β deposits in the brain parenchyma and cerebral vessels at this age, exhibit pre-activated platelets in the blood circulation accompanied by enhanced integrin αIIb β3 activation and degranulation of platelets compared to age-matched control mice [19]
This study showed that stimulation of human platelets from healthy donors by Aβ40 led to reactive oxygen species (ROS) and superoxide production, reduced mitochondrial transmembrane potential, induced the release of mitochondria from platelets and reduced the content of the mitochondrial protein the outer membrane 20 (TOM20)
Aβ40 aggregate formation in presence of platelets were comparable between APP23 mice and WT controls, which could be reduced upon treatment with vitamin C
Summary
The most prevalent form of dementia is Alzheimer’s disease (AD). AD is characterized by the pathological hallmarks of abnormal accumulation of amyloid β (Aβ) peptides in the brain [1]. One of the earliest pathological alterations in AD is the dysfunction of mitochondria [2] Mitochondrial abnormalities, such as impaired mitochondrial dynamics (increased fission and reduced fusion), altered morphology and mitochondrial gene expression, increased free radical production and lipid peroxidation, reduced cytochrome c oxidase (COX) activity and ATP production, are typical characteristics of AD. Different studies have identified pathological alterations in isolated platelets from AD patients, such as a decreased amyloid protein precursor ratio and an increased activity of β-secretase leading to. A subpopulation of coated platelets with high procoagulant activity is elevated in AD patients and correlates with the progression of AD [20] Apart from their ability to generate Aβ peptides, predominantly Aβ40, platelets modify soluble synthetic Aβ40 into toxic Aβ aggregates in vitro [15]. The present study aimed to investigate the effect of Aβ40 peptides on platelet mitochondrial dynamics and its consequences for platelet activation and Aβ40 aggregate formation
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