Reducing expression of synapse-restricting protein Ephexin5 ameliorates Alzheimer’s-like impairment in mice
Gabrielle L. Sell, … , Thomas B. Schaffer, Seth S. Margolis
Gabrielle L. Sell, … , Thomas B. Schaffer, Seth S. Margolis
Published March 27, 2017
Citation Information: J Clin Invest. 2017;127(5):1646-1650. https://doi.org/10.1172/JCI85504.
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Concise Communication Neuroscience

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

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.

Authors

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

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Figure 1

Ephexin5 expression is altered in response to Aβ and in AD.

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Ephexin5 expression is altered in response to Aβ and in AD. (A) Immunocy...
(A) Immunocytochemistry of Ephexin5 from cultured hippocampal neurons treated with control or Aβ peptide. Representative images are shown. Original magnification: ×40. Quantification indicates the intensity of Ephexin5 signal within GFP-filled neurons (n = 30 neurons from 3 independent experiments). *P < 0.05, by 2-tailed t test. Ephexin5 intensity is shown as Fold change in fluorescence intensity of Ephexin5 signal normalized to control. GFP neuron area is shown as fold change in fluorescence area normalized to control. (B) Western blot of whole hippocampal lysate after injection in vivo of Aβ1-42 or Aβ42-1, with actin used as a loading control. (C) Representative Western blot of Ephexin5 levels in lysed, microdissected WT (n = 7) and hAPP (n = 7) CA and DG regions of hippocampus. Ephexin5 levels were normalized to actin. (B and C) Quantification shows arbitrary densitometry units of Ephexin5 signal normalized to Actin loading. (D) Western blot of Ephexin5, EPHB2, TUBB3, and actin in human hippocampal samples (C = 3 independent controls; the other samples are marked by Braak stage). Quantifications were normalized to actin. Ephexin5, EPHB2 or TUBB3 signal each normalized to Actin loading (Arbitrary densitometry units). Data in D are reported in the box and whisker plot. *P < 0.05, by 1-way ANOVA with Dunnet’s correction.