Amyloid-β Causes Mitochondrial Dysfunction via a Ca2+-Driven Upregulation of Oxidative Phosphorylation and Superoxide Production in Cerebrovascular Endothelial Cells

Abstract

Cerebrovascular pathology is pervasive in Alzheimer's disease (AD), yet it is unknown whether cerebrovascular dysfunction contributes to the progression or etiology of AD. In human subjects and in animal models of AD, cerebral hypoperfusion and hypometabolism are reported to manifest during the early stages of the disease and persist for its duration. Amyloid-β is known to cause cellular injury in both neurons and endothelial cells by inducing the production of reactive oxygen species and disrupting intracellular Ca 2+ homeostasis. We present a mechanism for mitochondrial degeneration caused by the production of mitochondrial superoxide, which is driven by increased mitochondrial Ca 2+ uptake. We found that persistent superoxide production injures mitochondria and disrupts electron transport in cerebrovascular endothelial cells. These observations provide a mechanism for the mitochondrial deficits that contribute to cerebrovascular dysfunction in patients with AD.

Deltamethrin Induces Apoptosis in Cerebrum Neurons of Quail via Promoting Endoplasmic Reticulum Stress and Mitochondrial Dysfunction

“…With the gradual loss of ER function, ER will further release Ca 2+ into the cell cytoplasm (McFarland et al, 2020). High concentrations of Ca 2+ can directly act on mitochondria, causing mitochondrial dysfunction and triggering mitochondrial-related apoptosis (Quintana et al, 2020). However, the effect of DLM on intracellular Ca 2+ in cells of quail has not been reported to date.…”

Reactive Oxygen Species and Endothelial Ca2+ Signaling: Brothers in Arms or Partners in Crime?

“…For instance, Aβ 1-40 -induced oxidative stress in endothelial cells may inhibit Ach-induced, TRPV4-dependent EDH and vasodilation in cerebral arteries [ 295 ]. Furthermore, TRPM2-mediated extracellular Ca 2+ entry could accelerate mitochondrial oxygen consumption and boost mitochondrial production of O 2 • − , which further exacerbates Aβ 1-40 -induced endothelial dysfunction [ 56 ]. Furthermore, TRPM2 contributes to methamphetamine (METH)- and HIV-TAT-induced BBB injury [ 296 ].…”

“…Endothelial ROS signaling is exploited by mechanical and chemical cues to regulate a number of vascular functions that often overlap with those controlled by Ca 2+ , e.g., EDH [ 47 ], vascular permeability [ 48 ], leukocyte infiltration [ 49 ], platelet aggregation [ 50 ], gene expression [ 51 ], angiogenesis [ 45 , 52 ], and vasculogenesis [ 53 ]. Like Ca 2+ , deregulated ROS signaling impairs endothelial-mediated functions, thereby engendering potentially catastrophic consequences for the cardiovascular system [ 22 , 31 , 36 , 38 , 54 , 55 , 56 , 57 , 58 , 59 ]. The existence of a functional crosstalk between endothelial Ca 2+ and ROS signaling is further strengthened by the evidence that ROS may stimulate an increase in [Ca 2+ ] i [ 6 , 60 , 61 , 62 ] and that, vice versa, intracellular Ca 2+ signals may boost endogenous ROS production in vascular endothelium [ 57 , 63 , 64 ].…”

Blood–Brain Barrier and Neurovascular Unit In Vitro Models for Studying Mitochondria-Driven Molecular Mechanisms of Neurodegeneration

“…Aβ negatively affects mitochondrial activity in BMECs (suppression of OXPHOS and elevation of ROS production), and this effect is potentiated by high extracellular glucose levels resembling local insulin resistance in Alzheimer’s type neurodegeneration [ 116 ]. Disruption of Ca2+ homeostasis in BMECs caused by Aβ is accompanied by upregulation of OXPHOS (like in the inverse Warburg effect in neuronal cells described above) followed by overproduction of ROS, cell death, and development of cerebrovascular dysfunction [ 117 , 118 ]. Mitochondrial coenzyme Q10 pretreatment of ECs prevents Aβ accumulation in the cells, Ca2+ disturbances, ROS overproduction and mitochondrial dysfunction in the in vitro conditions [ 119 ].…”