Synaptic activity prompts γ-secretase–mediated cleavage of EphA4 and dendritic spine formation

Abstract

Alzheimer's disease is an age-dependent neurodegenerative disorder that is characterized by a progressive decline in cognitive function. γ-secretase dysfunction is evident in many cases of early onset familial Alzheimer's disease. However, the mechanism by which γ-secretase dysfunction results in memory loss and neurodegeneration is not fully understood. Here, we demonstrate that γ-secretase is localized at synapses and regulates spine formation. We identify EphA4, one of the Ephrin receptor family members, as a substrate of γ-secretase, and find that EphA4 processing is enhanced by synaptic activity. Moreover, overexpression of EphA4 intracellular domain increases the number of dendritic spines by activating the Rac signaling pathway. These findings reveal a function for EphA4-mediated intracellular signaling in the morphogenesis of dendritic spines and suggest that the processing of EphA4 by γ-secretase affects the pathogenesis of Alzheimer's disease.

β-Site Amyloid Precursor Protein (APP)-cleaving Enzyme 1 (BACE1)-deficient Mice Exhibit a Close Homolog of L1 (CHL1) Loss-of-function Phenotype Involving Axon Guidance Defects

“…3A). The broad spectrum matrix metalloprotease inhibitor GM6001 blocks ectodomain shedding of EphA4 (39), and ADAM8 and ADAM9 metalloproteases have been shown to process another member of the Eph receptor family, EphB4, to produce an NTF and a CTF (40,41). Therefore, we reasoned that the fragments we observed with EphA4 transfection alone were likely derived from ADAM (A Disinteg-rin and Metalloprotease) processing, in analogy to the ␣-secretase shedding of APP (42).…”

Genetic Evidence for a Contribution of EphA:EphrinA Reverse Signaling to Motor Axon Guidance

“…And what prevents motor axons from adhering to EphA4-positive mesenchymal cells, a process that could interfere with their further growth? One possibility is that EphA ectodomains are proteolytically cleaved (Inoue et al, 2009;Oricchio et al, 2011). Cleavage would eventually terminate EphA forward signaling in mesenchymal cells and allow motor axons to continue growing into the limb.…”

Reversing Synapse Loss in Alzheimer's Disease: Rho-Guanosine Triphosphatases and Insights from Other Brain Disorders

“…Aberrant Rac1 activity in AD could also be caused by abnormal EphA4 signaling. Indeed, EphA4 has been identified as a substrate for both β-secretase (BACE1) and γ-secretase [111,112]. EphA4 processing by γ-secretase upon increased synaptic activity generates EphA4 intracellular domain fragments, which trigger the formation of dendritic spines through a Rac1-dependent pathway.…”

“…EphA4 processing by γ-secretase upon increased synaptic activity generates EphA4 intracellular domain fragments, which trigger the formation of dendritic spines through a Rac1-dependent pathway. More importantly, AD-linked PS1 mutations (PS1M146L and PS1E280A) can impair EphA4 processing, resulting in reduced levels of EphA4 intracellular domain fragments and decrease Rac1/ PAK1 signaling [112]. The exact GEF/GAP involved is so far unknown, but the Rac1 GAP α2-chimaerin, which interacts with EphA4, may be a good candidate for future research [113].…”