Reducing expression of synapse-restricting protein Ephexin5 ameliorates Alzheimer's-like impairment in mice

Gabrielle L. Sell, Thomas B. Schaffer, Seth Shatkin Margolis

Research output: Contribution to journalArticle

Abstract

Accumulation of amyloid-β (Aβ) protein may cause synapse degeneration and cognitive impairment in Alzheimer's disease (AD) by reactivating expression of the developmental synapse repressor protein Ephexin5 (also known as ARHGEF15). Here, we have reported that Aβ is sufficient to acutely promote the production of Ephexin5 in mature hippocampal neurons and in mice expressing human amyloid precursor protein (hAPP mice), a model for familial AD that produces high brain levels of Aβ. Ephexin5 expression was highly elevated in the hippocampi of human AD patients, indicating its potential relevance to AD. We also observed elevated Ephexin5 expression in the hippocampi of hAPP mice. Removal of Ephexin5 expression eliminated hippocampal dendritic spine loss and rescued AD-associated behavioral deficits in the hAPP mice. Furthermore, selective reduction of Ephexin5 expression using shRNA in the dentate gyrus of presymptomatic adolescent hAPP mice was sufficient to protect these mice from developing cognitive impairment. Thus, pathological elevation of Ephexin5 expression critically drives Aβ-induced memory impairment, and strategies aimed at reducing Ephexin5 levels may represent an effective approach to treating AD.

Original languageEnglish (US)
Pages (from-to)1646-1650
Number of pages5
JournalJournal of Clinical Investigation
Volume127
Issue number5
DOIs
StatePublished - May 1 2017

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Synapses
Alzheimer Disease
Proteins
Hippocampus
Repressor Proteins
Serum Amyloid A Protein
Dendritic Spines
Amyloid beta-Protein Precursor
Dentate Gyrus
Small Interfering RNA
Neurons
Brain
Cognitive Dysfunction

ASJC Scopus subject areas

  • Medicine(all)

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Reducing expression of synapse-restricting protein Ephexin5 ameliorates Alzheimer's-like impairment in mice. / Sell, Gabrielle L.; Schaffer, Thomas B.; Margolis, Seth Shatkin.

In: Journal of Clinical Investigation, Vol. 127, No. 5, 01.05.2017, p. 1646-1650.

Research output: Contribution to journalArticle

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