Impact of Amyloid-β on Platelet Mitochondrial Function and Platelet–Mediated Amyloid Aggregation in Alzheimer’s Disease

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.

Effects of antidiabetic agents on platelet characteristics with implications in Alzheimer's disease: Mendelian randomization and colocalization study

“…In this regard, mitochondrial dysfunction has been demonstrated conducive to platelet-mediated Aβ aggregation in vitro [ 2 ]. Moreover, the alterations in the platelet amyloid precursor protein (APP) metabolic pathway in AD patients have been investigated and how Aβ elevated platelet activation, and activated platelets serve as a bridge between risk factors and AD have been further illustrated [ 4 ].…”

“…Based on the similarities between platelets and neuronal biology, it has been hypothesized that platelet-associated biological processes might be a part of the pathophysiological mechanism of AD. Platelets have been identified as the source of amyloid precursor proteins and Aβ peptides in the blood, contributing to the pathophysiology of AD by facilitating the formation of soluble Aβ into Aβ aggregates [ 2 , 3 ]. Increased platelet activation in AD has been reported in several studies [ 4 , 5 ].…”

Amyloid beta and tau protein metabolic changes detected by visible resonance Raman scattering microscopy in Alzheimer's disease mouse model

“…The research on Aβ protein in AD lesions has a history of more than 30 years [7]. The study of Aβ and tau protein in AD lesions with optical spectroscopy technology started in recent years [9][10][11][12][13][14][15][16][17]. Typical results of Aβ and tau protein studies in both AD lesion and control tissues are evidence of VRR spectroscopy technology as shown in Fig.…”

“…In 1996, the presence of β-amyloid protein structure in human Alzheimer's disease brain tissue using Fourier-transform infrared (FTIR) micro-spectroscopic technique was first reported [9]. Ultraviolet (UV), surface-enhanced Raman scattering (SERS), FTIR and stimulated Raman scattering (SRS) technologies have new results in the studies of Aβ plaque [10][11][12][13][14][15] and tau protein phosphorylation [16][17] of AD lesion of human and animal brain tissues.…”

Platelet-derived microparticles provoke chronic lymphocytic leukemia malignancy through metabolic reprogramming

“…Since mitochondria are sensitive to temperature changes, cycles of freezing and thawing causes damage to their function thus impairing the motility, plasma membrane integrity and mitochondria function of boar spermatozoa through generating excessive ROS (62). The second strategy was treating the PMPs with ROT/AmA compounds, as the mitochondrial respiratory chain complex I and III inhibitors, before co-incubation with the CLL cell groups (63,64). Upon co-incubation of leukemic cells with frozen-thawed PMPs, we observed no significant impact on cell viability in comparison to non-treated control cells (Supplementary Figure 2A).…”