Dataset Information

Amyloid β aggregation induces human brain microvascular endothelial cell death with abnormal actin organization.

ABSTRACT: Cerebral amyloid angiopathy (CAA) is a disease in which amyloid β (Aβ) is deposited on the walls of blood vessels in the brain, making those walls brittle and causing cerebral hemorrhage. However, the mechanism underlying its onset is not well understood. The aggregation and accumulation of Aβ cause the occlusion and fragility of blood vessels due to endothelial cell damage, breakdown of the blood-brain barrier, and replacement with elements constituting the blood vessel wall. In this study, we observed the effect of Aβ on human primary brain microvascular endothelial cells (hBMECs) in real-time using quantum dot nanoprobes to elucidate the mechanism of vascular weakening by Aβ. It was observed that Aβ began to aggregate around hBMECs after the start of incubation and that the cells were covered with aggregates. Aβ aggregates firmly anchored the cells on the plate surface, and eventually suppressed cell motility and caused cell death. Furthermore, Aβ aggregation induced the organization of abnormal actin, resulting in a significant increase in intracellular actin dots over 10 μm². These results suggest that the mechanism by which Aβ forms a fragile vessel wall is as follows: Aβ aggregation around vascular endothelial cells anchors them to the substrate, induces abnormal actin organization, and leads to cell death.

SUBMITTER: Take Y

PROVIDER: S-EPMC8685982 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Amyloid β aggregation induces human brain microvascular endothelial cell death with abnormal actin organization.

Take Yushiro Y Chikai Yusaku Y Shimamori Keiya K Kuragano Masahiro M Kurita Hiroki H Tokuraku Kiyotaka K

Biochemistry and biophysics reports 20211215

Cerebral amyloid angiopathy (CAA) is a disease in which amyloid β (Aβ) is deposited on the walls of blood vessels in the brain, making those walls brittle and causing cerebral hemorrhage. However, the mechanism underlying its onset is not well understood. The aggregation and accumulation of Aβ cause the occlusion and fragility of blood vessels due to endothelial cell damage, breakdown of the blood-brain barrier, and replacement with elements constituting the blood vessel wall. In this study, we ...[more]

PMID: 34977364

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Project description:Aging is the most important risk factor for neurodegenerative diseases associated with pathological protein aggregation such as Alzheimer's disease. Although aging is an important player, it remains unknown which molecular changes are relevant for disease initiation. Recently, it has become apparent that widespread protein aggregation is a common feature of aging. Indeed, several studies demonstrate that 100s of proteins become highly insoluble with age, in the absence of obvious disease processes. Yet it remains unclear how these misfolded proteins aggregating with age affect neurodegenerative diseases. Importantly, several of these aggregation-prone proteins are found as minor components in disease-associated hallmark aggregates such as amyloid-β plaques or neurofibrillary tangles. This co-localization raises the possibility that age-dependent protein aggregation directly contributes to pathological aggregation. Here, we show for the first time that highly insoluble proteins from aged Caenorhabditis elegans or aged mouse brains, but not from young individuals, can initiate amyloid-β aggregation in vitro. We tested the seeding potential at four different ages across the adult lifespan of C. elegans. Significantly, protein aggregates formed during the early stages of aging did not act as seeds for amyloid-β aggregation. Instead, we found that changes in protein aggregation occurring during middle-age initiated amyloid-β aggregation. Mass spectrometry analysis revealed several late-aggregating proteins that were previously identified as minor components of amyloid-β plaques and neurofibrillary tangles such as 14-3-3, Ubiquitin-like modifier-activating enzyme 1 and Lamin A/C, highlighting these as strong candidates for cross-seeding. Overall, we demonstrate that widespread protein misfolding and aggregation with age could be critical for the initiation of pathogenesis, and thus should be targeted by therapeutic strategies to alleviate neurodegenerative diseases.

Dataset Information

Amyloid β aggregation induces human brain microvascular endothelial cell death with abnormal actin organization.

Publications

Amyloid β aggregation induces human brain microvascular endothelial cell death with abnormal actin organization.

Similar Datasets

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