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.

A New Kid on the Block? Carbonic Anhydrases as Possible New Targets in Alzheimer’s Disease

“…The main pathological features of AD—amyloid-β (Aβ) plaques, neurofibrillary tangles (NFTs), astrogliosis and neuronal loss—were described by Alois Alzheimer in 1906 [4]. Microgliosis, inflammation, oxidative stress, major synaptic alteration and cerebral amyloid angiopathy are other pathological hallmarks of AD [5,6,7,8]. The sequential cleavage of amyloid protein precursor (APP) by β- and γ-secretases originates the Aβ peptide.…”

Engineered tissues and strategies to overcome challenges in drug development

“…The non-cell-autonomous nature also increases the likelihood that animal models will be poor representations of the disease, as the pathologic degeneration is dependent on the failure of multiple cell types all in a manner that is similar to human biology. For example, mouse models of Alzheimer's Disease readily form amyloid plaques, a hypothesized combined failure of brain endothelium and microglia [ 94 , 95 ], but fail to progress to the neuronal tauopathies observed in human patients [ 96 ]. Putative new models for degenerative diseases require access to disease-relevant human cell types and the ability to study them in the complex multicellular environments in which these diseases occur.…”

Signalling, Metabolic Pathways and Iron Homeostasis in Endothelial Cells in Health, Atherosclerosis and Alzheimer’s Disease

“…In addition to β-amyloid (Aβ) and tau pathobiology, cerebrovascular dysfunction and vascular pathology contribute to AD and increasing evidence strongly suggests that cerebrovascular dysfunction and vascular pathology is not merely a comorbidity but vascular damage and disfunction occurs either before [ 302 ] or in parallel of the accumulation of Aβ [ 302 , 303 , 304 ]. These studies suggest that endothelial dysfunction possibly initiates AD pathogenesis.…”