Referenced in: none

Automatically associated channels: TRP , TRPM , TRPM2

Title: The key role of transient receptor potential melastatin-2 channels in amyloid-β-induced neurovascular dysfunction.

Authors: L Park, G Wang, J Moore, H Girouard, P Zhou, J Anrather, C Iadecola

Journal, date & volume: Nat Commun, 2014 , 5, 5318

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25351853

Abstract
Alzheimer's dementia is a devastating and incurable disease afflicting over 35 million people worldwide. Amyloid-β (Aβ), a key pathogenic factor in this disease, has potent cerebrovascular effects that contribute to brain dysfunction underlying dementia by limiting the delivery of oxygen and glucose to the working brain. However, the downstream pathways responsible for the vascular alterations remain unclear. Here we report that the cerebrovascular dysfunction induced by Aβ is mediated by DNA damage caused by vascular oxidative-nitrosative stress in cerebral endothelial cells, which, in turn, activates the DNA repair enzyme poly(ADP)-ribose polymerase. The resulting increase in ADP ribose opens transient receptor potential melastatin-2 (TRPM2) channels in endothelial cells leading to intracellular Ca(2+) overload and endothelial dysfunction. The findings provide evidence for a previously unrecognized mechanism by which Aβ impairs neurovascular regulation and suggest that TRPM2 channels are a potential therapeutic target to counteract cerebrovascular dysfunction in Alzheimer's dementia and related pathologies.