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

Article type: Research Article

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.^{; *}

Affiliations: Department of Neuroscience, Center of Basic and Translational Stroke Research, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, USA

Correspondence: [*] Correspondence to: James W. Simpkins, PhD, Department of Physiology and Pharmacology, West Virginia University School of Medicine, 64 Medical Center Drive, Morgantown, WV 26501, USA. Tel.: +1 304 293 7430; E-mail: jwsimpkins@hsc.wvu.edu.

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 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.

Keywords: Amyloid-β, calcium, mitochondria, superoxide, vascular endothelial cells

DOI: 10.3233/JAD-190964

Journal: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 119-138, 2020