The Alzheimer’s disease risk gene CD2AP functions in dendritic spines by remodelling F-actin

Abstract

AbstractCD2AP was identified as a genetic risk factor for late-onset Alzheimer’s disease (LOAD). However, how CD2AP contributes to LOAD synaptic dysfunction underlying AD memory deficits is unclear. We have shown that CD2AP loss-of-function increases β-amyloid (Aβ) endocytic production, but whether it contributes to synapse dysfunction is unknown. Because CD2AP is an actin-binding protein, it may also function in F-actin-rich dendritic spines, the excitatory postsynaptic compartment. Here, we demonstrate that CD2AP colocalises with F-actin in dendritic spines. Cell-autonomous depletion of CD2AP specifically reduces spine density and volume, with a functional decrease in synapse formation and neuronal network activity. Post-synaptic reexpression of CD2AP but not blocking Aβ-production is sufficient to rescue spine density. CD2AP overexpression increases spine density, volume, and synapse formation, while a rare LOAD CD2AP mutation induces aberrant F-actin spine-like protrusions without synapses. CD2AP controls postsynaptic actin turnover, with the LOAD mutation in CD2AP decreasing F-actin dynamicity. Our data support that CD2AP risk variants could contribute to LOAD synapse dysfunction by disrupting spine formation and growth by deregulating actin dynamics.Graphical abstract