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
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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 3

Lentiviral manipulation of Ephexin5 in the DG ameliorates learning and memory deficits in developing hAPP mice.

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Lentiviral manipulation of Ephexin5 in the DG ameliorates learning and m...
(A) Timeline for the injection of WT and AD mice with lentivirus. (B) Representative immunofluorescence staining of the DG from a mouse injected with lentivirus. Sections were stained for GFP and labeled with DAPI. Scale bars: 10 μm. (C) Representative Western blot and quantification of actin-normalized Ephexin5 levels in microdissected hippocampi from mice injected with lentivirus expressing shRNA against Ephexin5 (E5) or scrambled hairpin (Scr). n = 7 mice. (D) NPP testing of object investigation for 3-month-old mice. Shown is the percentage time spent investigating each object, calculated as described in the legend for Figure 2. WT-Scr (n = 8), hAPP-Scr (n = 8), hAPP-E5 (n = 10), WT-E5 (n = 10). (C and D) *P < 0.05 and **P < 0.01. For comparison of lentivirus-injected hippocampal Ephexin5 levels, a paired t test was performed (C). Analysis of the NPP test was performed by 1-way ANOVA with a Kruskal-Wallis correction, since the data were not normally distributed (D).