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

Abstract

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.

Keywords: Alzheimer’s disease; amyloid; apoptosis; blood-brain barrier; cerebral amyloid angiopathy; endothelial cells; mitochondria; neurodegeneration; reactive nitrogen species; reactive oxygen species.

Fig. 1.

Nitric oxide and amyloid in vascular dysfunction. Endothelial NO is primarily responsible for mediating vasodilation through its actions on vascular smooth muscle cells. NO is synthesized by Ca²⁺-dependent eNOS and nNOS, and inflammation-induced iNOS. Both, inflammation and the increase in cytosolic Ca²⁺ increase NO production. Amyloid induces vascular dysfunction by promoting vasoconstriction through a direct action on vascular cells or through its effects on mitochondrial function. Amyloid also induces endothelial mitochondrial dysfunction, which results in excessive production of superoxide and a disruption of Ca²⁺ homeostasis. Mitochondria-produced superoxide spontaneously reacts with NO to form reactive peroxynitrite, reducing the NO pool and further contributing to vasoconstriction.

Fig. 2.

Amyloid-induced apoptotic pathways involving the mitochondria in cerebral endothelial cells. Various Aβ peptides have been shown to induce mitochondria-mediated extrinsic and intrinsic apoptosis in CECs. This figure depicts the effects of Aβ on membrane receptors, such as RAGE, CD36, and DR4/5, which activate both mitochondria-dependent and independent caspases (Cas) and apoptosis. Both Aβ₄₀ and Aβ₄₂ increase mitochondrial and cytosolic ROS, and mitochondrial CytC release. Aβ peptides can also activate PP2A-mediated cascade signaling and inhibit Akt, leading to the activation of pro-apoptotic proteins in the cytosol and mitochondria. Aβ also induces mitochondrial DNA damage that facilitates CEC apoptosis.