The Alzheimer's disease risk gene CD2AP modulates mammalian synaptic structure and plasticity

Abstract

CD2-Associated protein (CD2AP) is associated with increased risk of late-onset Alzheimer's disease. We have previously shown that loss of CD2AP's Drosophila homolog, cindr, exacerbates Tau toxicity and impairs synaptic maturation and function at the neuromuscular junction. However, little is understood about CD2AP at the central mammalian synapse. The present study demonstrates conservation of CD2AP function at the pre-synapse from fly to mouse, as well as characterizes CD2AP's role in maintaining post-synaptic structure and function.We examine short- and long-term plasticity using electrophysiologic measurements and synaptic structure and morphology using confocal imaging. Experiments were performed on homozygous CD2AP knockout mice and heterozygous CD2AP knockout mice to investigate potential haploinsufficient requirement. Mice constitutively expressing Cas9 endonuclease were used for brain-specific CD2AP knockout.Homozygous and heterozygous CD2AP knockout mice exhibit increased paired-pulse facilitation, a form of short-term plasticity. This matches data from Drosophila, implying conservation from fly to mouse, and indicates decreased probability of presynaptic vesicle release with CD2AP loss. We found no change in long-term potentiation (LTP) at 4 to 6 weeks; however, our preliminary experiments demonstrate decreased LTP in aged heterozygous CD2AP knockouts. Ongoing experiments are investigating age as a factor in CD2AP function. Lastly, CD2AP knockout neurons exhibit increased dendritic branching and homozygous knockout mice have increased expression of postsynaptic density protein 95.Our analyses implicate CD2AP in modulation of synaptic plasticity and structure, suggest a conservation of CD2AP function from flies to mice, and support CD2AP haploinsufficiency. Going forward, we will investigate how CD2AP loss affects existing Alzheimer's pathogenesis in a P301S tauopathy mouse model.