Insights into caspase-mediated apoptotic pathways induced by amyloid-β in cerebral microvascular endothelial cells

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Cerebral amyloid angiopathy (CAA) is an age-related condition linked to Alzheimer's disease, characterized by amyloid-beta (Aβ) deposition in cerebral vasculature.
• CAA impairs cerebral blood flow, leading to hemorrhages and cognitive decline, yet mechanisms of vascular cell degeneration remain unclear.
• The E22Q variant of amyloid-beta (Aβ) is strongly associated with CAA and severe cerebral hemorrhages.

Purpose of the Study:

• To elucidate the molecular pathways driving apoptosis in cerebral endothelial cells exposed to wild-type Aβ40 and the vasculotropic E22Q Aβ variant.
• Investigate the role of specific apoptotic signaling cascades in response to Aβ peptide aggregation.

Main Methods:

• Human brain microvascular endothelial cells were treated with wild-type Aβ40 and the E22Q Aβ variant.
• Apoptotic pathways activated by these Aβ variants were analyzed.

Main Results:

• Both Aβ variants induced caspase-mediated apoptosis, with timing related to their aggregation into oligomers and protofibrils.
• A primary activation of caspase-8, typically associated with death receptors, was observed, followed by caspase-9 activation.
• Mitochondrial release of cytochrome C and apoptosis-inducing factor indicated engagement of both extrinsic and intrinsic apoptotic pathways.

Conclusions:

• Amyloid-beta (Aβ) oligomers and protofibrils induce apoptosis in vascular cells via caspase-8 and caspase-9 dependent mitochondrial pathways.
• These findings suggest a primary activation of death receptors by Aβ in CAA pathogenesis.