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

• Published in: Journal of Alzheimer's disease Vol. 75; no. 1; p. 119
• Main Authors: Quintana, Dominic D, Garcia, Jorge A, Anantula, Yamini, Rellick, Stephanie L, Engler-Chiurazzi, Elizabeth B, Sarkar, Saumyendra N, Brown, Candice M, Simpkins, James W
• Format: Journal Article
• Language: English
• Published: Netherlands 01.01.2020
• Subjects: Amyloid beta-Peptides - pharmacology; Animals; Brain - drug effects; Brain - metabolism; Calcium - metabolism; Cell Line; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Mice; Mitochondria - drug effects; Mitochondria - metabolism; Oxidative Phosphorylation; Peptide Fragments - pharmacology; Reactive Oxygen Species - metabolism; Superoxides - metabolism; Up-Regulation - drug effects; vascular endothelial cells; calcium; Amyloid-β; superoxide; mitochondria
• ISSN: 1875-8908
• DOI: 10.3233/JAD-190964

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 Ca2+ homeostasis. We present a mechanism for mitochondrial degeneration caused by the production of mitochondrial superoxide, which is driven by increased mitochondrial Ca2+ 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.