Dissecting the Crosstalk between Endothelial Mitochondrial Damage, Vascular Inflammation, and Neurodegeneration in Cerebral Amyloid Angiopathy and Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is the most prevalent cause of dementia and is pathologically characterized by the presence of parenchymal senile plaques composed of amyloid β (Aβ) and intraneuronal neurofibrillary tangles of hyperphosphorylated tau protein. The accumulation of Aβ also occurs within the cerebral vasculature in over 80% of AD patients and in non-demented individuals, a condition called cerebral amyloid angiopathy (CAA). The development of CAA is associated with neurovascular dysfunction, blood–brain barrier (BBB) leakage, and persistent vascular- and neuro-inflammation, eventually leading to neurodegeneration. Although pathologically AD and CAA are well characterized diseases, the chronology of molecular changes that lead to their development is still unclear. Substantial evidence demonstrates defects in mitochondrial function in various cells of the neurovascular unit as well as in the brain parenchyma during the early stages of AD and CAA. Dysfunctional mitochondria release danger-associated molecular patterns (DAMPs) that activate a wide range of inflammatory pathways. In this review, we gather evidence to postulate a crucial role of the mitochondria, specifically of cerebral endothelial cells, as sensors and initiators of Aβ-induced vascular inflammation. The activated vasculature recruits circulating immune cells into the brain parenchyma, leading to the development of neuroinflammation and neurodegeneration in AD and CAA.

Beta-Amyloid Instigates Dysfunction of Mitochondria in Cardiac Cells

“…Alternatively, extracellular oligomeric Aβ aggregates may affect mitochondrial function by triggering cell membrane receptors (e.g., death receptors) and/or other signal transduction pathways that converge on the mitochondria [19]. Aβ has been shown by many studies, including ours, to diminish mitochondrial respiration and increase the levels of mtROS in multiple cell types, including neuronal and cerebral endothelial cells [19,21,24,25,34,43], and thus, can induce further Aβ and tau protein production [4]. However, there are few if any studies that investigate the direct effects of Aβ on cardiomyocytes and coronary endothelial cells.…”

SARS-CoV-2 infection of human brain microvascular endothelial cells leads to inflammatory activation through NF-κB non-canonical pathway and mitochondrial remodeling

“…Our final series of experiments focused on mitochondrial morphology and dynamics in HBMECs following SARS-CoV-2 infection. It is well known that mitochondria are gatekeepers of BBB endothelium physiology and correspond to higher cytoplasmic volume as compared to non-cerebrovascular endothelial cells (Oldendorf et al, 1977; reviewed by Parodi-Rullan et al, 2021). Moreover, mitochondrial function is important for BBB maintenance and integrity (Doll et al, 2015).…”

Perivascular spaces visible on magnetic resonance imaging predict subsequent delirium in older patients

“…Abnormal protein aggregation (e.g., β-amyloid) can block the upstream within the cortical arteries and impair the external drainage of interstitial fluid in the deep white matter, thus contributing to the retrograde enlargement of PVS in CS ( Gouveia-Freitas and Bastos-Leite, 2021 ), and the relationship between β-amyloid accumulation and CS-PVS has been demonstrated in previous studies ( Roher et al, 2003 ; Charidimou et al, 2015 ). Furthermore, the impaired perivascular pathway may cause a vicious feed-forward cycle, further prompting PVS dysfunction and β-amyloid deposition in the vascular wall and brain ( Gouveia-Freitas and Bastos-Leite, 2021 ; Bown et al, 2022 ), which may exacerbate neurovascular dysfunction, neuroinflammation, and neurodegeneration ( Carrano et al, 2012 ; Parodi-Rullan et al, 2021 ), making the brain vulnerable to delirium ( Idland et al, 2017 ; Maldonado, 2018 ; Chan et al, 2021 ).…”

“…BG-PVS, basal ganglia perivascular space; CS-PVS, centrum semiovale perivascular space; CI, confidence interval. cause a vicious feed-forward cycle, further prompting PVS dysfunction and β-amyloid deposition in the vascular wall and brain (Gouveia-Freitas and Bastos-Leite, 2021;Bown et al, 2022), which may exacerbate neurovascular dysfunction, neuroinflammation, and neurodegeneration (Carrano et al, 2012;Parodi-Rullan et al, 2021), making the brain vulnerable to delirium (Idland et al, 2017;Maldonado, 2018;Chan et al, 2021).…”