Ephexin5, negative regulator of dendritic spine formation, contributes to hippocampal-dependent phenotypes in both Alzheimer’s disease and Angelman syndrome models
Embargo until
2019-05-01
Date
2017-12-19
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Johns Hopkins University
Abstract
The human condition is plagued with disease, none of which is so least understood as neurological disease. Given the complexity of the brain, it is no surprise that there are few treatments. Many human neurodegenerative and neurodevelopmental disorders are characterized by a profound alteration in dendritic spine number or morphology, including Alzheimer’s disease (AD) and Angelman syndrome (AS). Dendritic spines are protrusions from neuronal processes that house 95% of excitatory synapses, sites of neuronal communication. Molecules which promote the formation, stability, or strength of synapses on dendritic spines have been consistently studied and associated with disease, while molecules which negatively regulate these processes are less well characterized. We discovered that the developmental negative regulator of dendritic spine formation, Ephexin5, acts to mediate pathways that lead to phenotypes observed in AD and AS mouse models. The basis of this discovery stems from previous findings that Ephexin5 associates with and is regulated by EphB2 and UBE3A, two enzymes shown to be causative to AD and AS, respectively. To determine the role Ephexin5 plays in these diseased mice, we utilized biochemical protein analysis, electrophysiological recordings, in vivo and in vitro spine analysis, and numerous behavioral assays. Here we show Ephexin5 protein was found to be upregulated in human AD hippocampus, and this was replicated in a mouse model of AD, and in response to Aβ42 in vivo and in vitro. Removal of Ephexin5 in these mice was sufficient to prevent spine decreases as well as learning and memory deficits, while partially rescuing LTP induction in hippocampus. Reduction of Ephexin5 via lentiviral-mediated shRNA knockdown directly into dentate gyrus was sufficient to replicate this learning and memory rescue. In a separate but similar study, we found that Ephexin5 was increased in AS mouse hippocampus. Removal of Ephexin5 was sufficient to rescue novel object testing and normalize spine density and mEPSCs in AS mice back to wild type levels. These data indicate that Ephexin5 is capable of modulating disease behavioral, cell biological, and electrophysiological phenotypes. Therefore, we found Ephexin5 could be a potential therapeutic target for a broad spectrum of brain disorders with underlying spine density deficits.
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Keywords
Alzheimer's disease, neurodegeneration, Angelman syndrome, synapse, dendritic spines, hippocampus, Ephexin5, RhoA GEF, Ube3A, EphB2