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

TitleThe key role of transient receptor potential melastatin-2 channels in amyloid-β-induced neurovascular dysfunction.
Publication TypeJournal Article
Year of Publication2014
AuthorsPark L, Wang G, Moore J, Girouard H, Zhou P, Anrather J, Iadecola C
JournalNat Commun
Volume5
Pagination5318
Date Published2014 Oct 29
ISSN2041-1723
KeywordsAmyloid beta-Peptides, Animals, Brain, Calcium, Cerebrovascular Circulation, DNA Damage, Endothelial Cells, Enzyme Activation, Enzyme Inhibitors, Glycoside Hydrolases, Ion Channel Gating, Mice, Transgenic, Microvessels, Nervous System, Nitrosation, Peroxynitrous Acid, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases, Stress, Physiological, TRPM Cation Channels, Vasomotor System
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.

DOI10.1038/ncomms6318
Alternate JournalNat Commun
PubMed ID25351853
PubMed Central IDPMC4283829
Grant ListR01 NS034179 / NS / NINDS NIH HHS / United States
R01 NS037853 / NS / NINDS NIH HHS / United States
NS37853 / NS / NINDS NIH HHS / United States