Amyloid beta oligomers trigger death receptors‐mediated apoptosis in cerebral endothelial cells

Abstract

Vascular deposition of Aβ in sporadic and familial Alzheimer's disease, through poorly understood molecular mechanisms, leads to alterations in cerebral blood flow, focal ischemia, and cerebral micro‐/macro‐hemorrhages, significantly contributing to cognitive impairment. We aimed to determine the molecular mechanisms triggering apoptosis of vessel wall cells in presence of Aβ40 or its vasculotropic variants E22Q or L34V. Challenging human brain microvascular endothelial cells with both variants and wild‐type Aβ40, we showed that TRAIL death receptors DR4 and DR5 specifically mediate oligomeric Aβ induction of extrinsic apoptotic pathways. Caspase‐8 activation preceded activation of caspase‐9. The caspase‐8 inhibitor cFLIP was downregulated, and mitochondrial paths were engaged through BID cleavage. Up‐regulation of DR4 and DR5 and co‐localization with Aβ at the cell membrane suggested their involvement as initiators of the apoptotic machinery. Direct binding assays using receptor chimeras confirmed the specific interaction of oligomeric Aβ with DR4 and DR5 whereas apoptosis protection achieved through RNA silencing of both receptors highlighted their active role in downstream apoptotic pathways unveiling new targets for therapeutic intervention.Support: NIH AG30539, NS051715, American Heart and Alzheimer's Associations.