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MITOCHONDRIAL MECHANISMS AND CARBONIC ANHYDRASES MEDIATE NEUROVASCULAR DYSFUNCTION IN CAA MODELS

Fossati, Silvia
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1905-07-16
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https://scholarshare.temple.edu/handle/20.500.12613/11645
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https://doi.org/10.1016/j.cccb.2022.100122
Abstract
Cerebrovascular dysfunction is one of the earliest events in Alzheimer's disease (AD) pathogenesis. Amyloid beta (Aβ) vascular deposits known as cerebral amyloid angiopathy (CAA) as well as chronic cardiovascular (CV) risk factors are known to affect endothelial cell (EC) physiology, blood brain barrier (BBB) permeability, and neurovascular (NV) health. However, the mechanisms responsible for endothelial and vascular dysfunction in AD and CAA are still poorly understood, and strategies to prevent neurovascular unit (NVU) failure are urgently needed. Using human cerebral vascular cells in culture and mouse models of vascular amyloidosis we are clarifying cell stress mechanisms by which different amyloid species, as well as cardiovascular risk factors, affect ECs and the NVU. We tested apoptotic cell death mechanisms, mitochondrial dysfunction, BBB resistance and angiogenesis in vitro, and NV cell stress and inflammation in vivo. We also assessed the participation of carbonic anhydrases (CAs), ubiquitous enzymes catalyzing the reversible hydration of carbon dioxide and implicated in mitochondrial function, in these events, and the ability of CA inhibitors to ameliorate NV dysfunction. Aβ peptides and aggregation species induced mitochondria and death receptor-mediated apoptotic EC death and BBB permeability. CV risk factors such as high-homocysteine or hypoxia potentiated the effects of Aβ on specific mechanisms of EC dysfunction. The deleterious effects of Aβ in ECs were counteracted by CA inhibition or silencing. Our studies in the TgSwDI mouse model of vascular amyloidosis showed that NV cell stress, neuroinflammation, vascular and immune cell-specific caspase activation, and memory impairment were all diminished by CA inhibitors.
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Silvia fossati, MITOCHONDRIAL MECHANISMS AND CARBONIC ANHYDRASES MEDIATE NEUROVASCULAR DYSFUNCTION IN CAA MODELS, Cerebral Circulation - Cognition and Behavior, Volume 6, 2024, 100122, ISSN 2666-2450, https://doi.org/10.1016/j.cccb.2022.100122. (https://www.sciencedirect.com/science/article/pii/S2666245022000873)
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Elsevier
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Cerebral Circulation - Cognition and Behavior, Vol. 6
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