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Amyloid β aggregation induces human brain microvascular endothelial cell death with abnormal actin organization
Yushiro Take1,2,3, Yusaku Chikai1, Keiya Shimamori1
1Graduate School of Engineering, Muroran Institute of Technology, Hokkaido, 050-8585, Japan.
Insights
Amyloid beta (Aβ) aggregation damages brain blood vessels by anchoring endothelial cells, disrupting actin, and causing cell death. This study reveals key mechanisms behind cerebral amyloid angiopathy (CAA) fragility.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Cerebral amyloid angiopathy (CAA) involves amyloid beta (Aβ) deposition in brain blood vessels, leading to fragility and hemorrhage.
- The precise mechanisms driving vascular weakening in CAA remain unclear.
- Aβ accumulation contributes to blood vessel occlusion, endothelial cell damage, and blood-brain barrier breakdown.
Purpose of the Study:
- To investigate the real-time effects of amyloid beta (Aβ) on human primary brain microvascular endothelial cells (hBMECs).
- To elucidate the molecular mechanisms underlying Aβ-induced vascular weakening in cerebral amyloid angiopathy (CAA).
Main Methods:
- Utilized quantum dot nanoprobes for real-time observation of Aβ interactions with hBMECs.
- Monitored Aβ aggregation, cell adhesion, motility, and cell death.
- Quantified intracellular actin organization and changes in actin dots.
Main Results:
- Observed Aβ aggregation around hBMECs, leading to cell coverage.
- Found that Aβ aggregates anchored cells to the substrate, suppressed motility, and induced cell death.
- Demonstrated that Aβ aggregation caused abnormal actin organization, significantly increasing intracellular actin dots.
Conclusions:
- Aβ aggregation around vascular endothelial cells anchors them, disrupting normal function.
- Abnormal actin organization and subsequent cell death are key mechanisms in Aβ-induced vascular fragility.
- These findings provide insights into the pathogenesis of cerebral amyloid angiopathy (CAA).
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.
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