Neuronal store-operated calcium entry and mushroom spine loss in amyloid precursor protein knock-in mouse model of Alzheimer’s disease

Hua Zhang, Lili Wu, Ekaterina Pchitskaya, Olga Zakharova, Takashi Saito, Takaomi Saido, Ilya Bezprozvanny

Research output: Contribution to journalArticle

86 Scopus citations

Abstract

Alzheimer’s disease (AD) is the most common reason for elderly dementia in the world. We proposed that memory loss in AD is related to destabilization of mushroom postsynaptic spines involved in long-term memory storage. We demonstrated previously that stromal interaction molecule 2 (STIM2)-regulated neuronal store-operated calcium entry (nSOC) in postsynaptic spines play a key role in stability of mushroom spines by maintaining activity of synaptic Ca2+/calmodulin kinase II (CaMKII). Furthermore, we demonstrated previously that the STIM2–nSOC–CaMKII pathway is downregulated in presenilin 1 M146V knock-in (PS1–M146V KI) mouse model of AD, leading to loss of hippocampal mushroom spines in this model. In the present study, we demonstrate that hippocampal mushroom postsynaptic spines are also lost in amyloid precursor protein knock-in (APPKI) mouse model of AD. We demonstrated that loss of mushroom spines occurs as a result of accumulation of extracellular β-amyloid 42 in APPKI culture media. Our results indicate that extracellular Aβ42 acts by overactivating mGluR5 receptor in APPKI neurons, leading to elevated Ca2+ levels in endoplasmic reticulum, compensatory downregulation of STIM2 expression, impaired synaptic nSOC, and reduced CaMKII activity. Pharmacological inhibition of mGluR5 or overexpression of STIM2 rescued synaptic nSOC and prevented mushroom spine loss in APPKI hippocampal neurons. Our results indicate that downregulation of synaptic STIM2–nSOC–CaMKII pathway causes loss ofmushroomsynaptic spines in both presenilin and APPKI mouse models of AD.Wepropose that modulators/activators of this pathwaymayhave a potential therapeutic value for treatment of memory loss in AD.

Original languageEnglish (US)
Pages (from-to)13275-13286
Number of pages12
JournalJournal of Neuroscience
Volume35
Issue number39
DOIs
StatePublished - Sep 30 2015

Keywords

  • Calcium
  • Imaging
  • Synaptic
  • Transgenic

ASJC Scopus subject areas

  • Neuroscience(all)

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