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

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...

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Bibliographic Details
Published in:The Journal of clinical investigation 2017-05, Vol.127 (5), p.1646-1650
Main Authors: Sell, Gabrielle L, Schaffer, Thomas B, Margolis, Seth S
Format: Article
Language:English
Subjects:
Actin
Age
Alzheimer Disease - genetics
Alzheimer Disease - metabolism
Alzheimer Disease - pathology
Alzheimer Disease - physiopathology
Alzheimer's disease
Amyloid beta-Peptides - genetics
Amyloid beta-Peptides - metabolism
Amyloid beta-protein
Amyloid precursor protein
Animal models
Animals
Antibodies
Biomedical research
Brief Report
Caspase
Caspase-2
Cell death
Circuits
Clonal deletion
Cognitive ability
Cognitive Dysfunction - genetics
Cognitive Dysfunction - metabolism
Cognitive Dysfunction - pathology
Cognitive Dysfunction - physiopathology
Cortex
Cytoskeleton
Dendritic Spines - genetics
Dendritic Spines - metabolism
Dentate Gyrus - metabolism
Dentate Gyrus - pathology
Dentate Gyrus - physiopathology
Disease Models, Animal
Female
Gene expression
Gene Expression Regulation
Genetic aspects
Genotypes
Guanine Nucleotide Exchange Factors - biosynthesis
Guanine Nucleotide Exchange Factors - genetics
Hippocampus
Humans
Male
Memory
Mice
Mice, Knockout
Nervous system
Neurodegeneration
Neurodegenerative diseases
Neuroethology
Neurons
Pathogenesis
Proteins
Pseudopodia
Rodents
Studies
Synaptogenesis
Transgenic animals
Tumor suppressor genes
β-Amyloid
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Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI85504