Endothelial Mitochondrial Dysfunction in Cerebral Amyloid Angiopathy and Alzheimer’s Disease

Jul 16, 2019Journal of Alzheimer's disease : JAD

Mitochondrial Problems in Blood Vessel Cells in Brain Amyloid Build-Up and Alzheimer's Disease

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Abstract

Cerebral amyloid angiopathy (CAA) is observed in up to 90% of Alzheimer's disease patients.

Cerebrovascular dysfunction is an early event in the development of Alzheimer's disease and other dementias.
CAA involves amyloid deposits around blood vessels and contributes to vascular dysfunction in Alzheimer's disease.
Brain vessels affected by CAA exhibit dysfunctional blood flow and a leaky blood-brain barrier, impairing amyloid clearance.
Mitochondrial dysfunction is recognized as an early trigger in the pathogenesis of both Alzheimer's disease and CAA.
The review discusses how amyloid-β affects the function of brain microvascular cells, particularly endothelial mitochondria.

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Alzheimer's disease (AD) is the most prevalent form of dementia. Cerebrovascular dysfunction is one of the earliest events in the pathogenesis of AD, as well as in vascular and mixed dementias. Cerebral amyloid angiopathy (CAA), the deposition of amyloid around cerebral vessels, is observed in up to 90% of AD patients and in approximately 50% of elderly individuals over 80 years of age. CAA is a strong contributor to vascular dysfunction in AD. CAA-laden brain vessels are characterized by dysfunctional hemodynamics and leaky blood-brain barrier (BBB), contributing to clearance failure and further accumulation of amyloid-β (Aβ) in the cerebrovasculature and brain parenchyma. Mitochondrial dysfunction is increasingly recognized as an important early initiator of the pathogenesis of AD and CAA. The objective of this review is to discuss the effects of Aβ on cerebral microvascular cell function, focusing on its impact on endothelial mitochondria. After introducing CAA and its etiology and genetic risk factors, we describe the pathological relationship between cerebrovascular amyloidosis and brain microvascular endothelial cell dysfunction, critically analyzing its roles in disease progression, hypoperfusion, and BBB integrity. Then, we focus on discussing the effect of Aβ challenge on endothelial mitochondrial dysfunction pathways, and their contribution to the progression of neurovascular dysfunction in AD and dementia. Finally, we report potential pharmacological and non-pharmacological mitochondria-targeted therapeutic strategies which may help prevent or delay cerebrovascular failure.

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Endothelial Mitochondrial Dysfunction in Cerebral Amyloid Angiopathy and Alzheimer’s Disease

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