Store-operated calcium channel complex in postsynaptic spines: A new therapeutic target for alzheimer’s disease treatment

Hua Zhang, Suya Sun, Lili Wu, Ekaterina Pchitskaya, Olga Zakharova, Klementina Fon Tacer, Ilya Bezprozvanny

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Mushroom dendritic spine structures are essential for memory storage and the loss of mushroom spines may explain memory defects in aging and Alzheimer’s disease (AD). The stability of mushroom spines depends on stromal interaction molecule 2 (STIM2)-mediated neuronal-store-operated Ca2+influx (nSOC) pathway, which is compromised inADmouse models, in aging neurons, and in sporadicAD patients. Here, we demonstrate that the Transient Receptor Potential Canonical 6 (TRPC6) and Orai2 channels form a STIM2-regulated nSOC Ca2+ channel complex in hippocampal mushroom spines. We further demonstrate that a known TRPC6 activator, hyperforin, and a novel nSOC positive modulator, NSN21778 (NSN), can stimulate activity of nSOC pathway in the spines and rescue mushroom spine loss in both presenilin and APP knock-in mouse models of AD. We further show that NSN rescues hippocampal long-term potentiation impairment in APP knock-in mouse model. We conclude that the STIM2-regulated TRPC6/Orai2 nSOC channel complex in dendritic mushroom spines is a new therapeutic target for the treatment of memory loss in aging and AD and that NSN is a potential candidate molecule for therapeutic intervention in brain aging and AD.

Original languageEnglish (US)
Pages (from-to)11837-11850
Number of pages14
JournalJournal of Neuroscience
Volume36
Issue number47
DOIs
StatePublished - Nov 23 2016

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Keywords

  • Calcium
  • Channels
  • Dendrites
  • Hippocampus
  • Imaging
  • Synapse

ASJC Scopus subject areas

  • Neuroscience(all)

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