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 2

Removal of Ephexin5 prevents hippocampal spine density abnormalities and cognitive deficits in hAPP mice.

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Removal of Ephexin5 prevents hippocampal spine density abnormalities and...
(A) Representative dendrite segments from WT, hAPP, hAPP/E5–/–, and E5–/– DG. Scale bars: 2 μm. (B) DG total spine density. (C) DG mushroom/thin spine density. (A–C) n = 3/genotype. (B and C) **P < 0.007, by 1-way ANOVA with Tukey’s correction. (D) Object investigation in the NPP test for 2.5- to 4-month-old mice. Shown is the percentage of time spent investigating each object. The time spent with an individual object was divided by the total time spent investigating all objects and multiplied by 100. WT (n = 12), hAPP (n = 11), hAPP/E5–/– (n = 16), and E5–/– (n = 9) mice were tested. (E) Latency for 6- to 8-month-old mice to enter the shock arena on days 1 and 2. WT (n = 14), hAPP (n = 18), hAPP/E5–/– (n = 12), and E5–/– (n = 9) mice were tested. Data represent the mean ± SEM. (D and E) **P < 0.05 and ***P < 0.0001. Analysis of the NPP test was performed by 1-way ANOVA with a Kruskal-Wallis correction, since the data were not normally distributed. Comparisons for the PA test were made using 2-way ANOVA with a Holm-Sidak correction.