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bioRxiv · 10.1101/2023.08.31.555707

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

Mirfakhar, F. S.·Castanheira, J.·Domingues, R.·Ramalho, J. S.·Almeida, C.
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Abstract

CD2AP was identified as a genetic risk factor for late-onset Alzheimers 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 {beta}-amyloid (A{beta}) 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 A{beta}-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 O_FIG O_LINKSMALLFIG WIDTH=193 HEIGHT=200 SRC="FIGDIR/small/555707v1_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@160769org.highwire.dtl.DTLVardef@40b903org.highwire.dtl.DTLVardef@1327623org.highwire.dtl.DTLVardef@1ea0f1e_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Mirfakhar, F. S., Castanheira, J., Domingues, R., Ramalho, J. S., Almeida, C.. 2023-09-01. The Alzheimer's disease risk gene CD2AP functions in dendritic spines by remodelling F-actin. https://doi.org/10.1101/2023.08.31.555707

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