Alzheimer’s disease risk gene <i>CD2AP</i> is a dose-sensitive determinant of synaptic structure and plasticity
CD2-Associated protein (CD2AP) is a candidate susceptibility gene for Alzheimer's disease, but its role in the mammalian central nervous system remains largely unknown. We show that CD2AP protein is broadly expressed in the adult mouse brain, including within cortical and hippocampal neurons, where it is detected at pre-synaptic terminals. Deletion of Cd2ap altered dendritic branching and spine density, and impaired ubiquitin-proteasome system activity. Moreover, in mice harboring either one or two copies of a germline Cd2ap null allele, we noted increased paired-pulse facilitation at hippocampal Schaffer-collateral synapses, consistent with a haploinsufficient requirement for pre-synaptic release. Whereas conditional Cd2ap knockout in the brain revealed no gross behavioral deficits in either 3.5- or 12-month-old mice, Cd2ap heterozygous mice demonstrated subtle impairments in discrimination learning using a touchscreen task. Based on unbiased proteomics, partial or complete loss of Cd2ap triggered perturbation of proteins with roles in protein folding, lipid metabolism, proteostasis, and synaptic function. Overall, our results reveal conserved, dose-sensitive requirements for CD2AP in the maintenance of neuronal structure and function, including synaptic homeostasis and plasticity, and inform our understanding of possible cell-type specific mechanisms in Alzheimer's Disease.
Authors
- Surabi Veeraragavan (ORCID: https://orcid.org/0000-0002-7921-7944)
- Mikhail Y Kochukov (ORCID: https://orcid.org/0000-0002-8012-5246)
- Masashi Fujita (ORCID: https://orcid.org/0000-0002-1457-6233)
- Ruth B. De-Paula (ORCID: https://orcid.org/0000-0003-1022-2056)
- Evelyne K. Tantry (ORCID: https://orcid.org/0000-0002-1782-0692)
- Nicholas T. Seyfried (ORCID: https://orcid.org/0000-0002-4507-624X)
- Jason D. Heaney (ORCID: https://orcid.org/0000-0001-8475-8828)
- Matea Pavešković
- Shamsideen A. Ojelade
- Snigdha Srivastava (ORCID: https://orcid.org/0000-0002-6761-0714)
- Siyuan Song (ORCID: https://orcid.org/0000-0002-6872-1360)
- Benjamin Russell Arenkiel (ORCID: https://orcid.org/0000-0001-9047-2420)
- Philip L. De Jager (ORCID: https://orcid.org/0000-0002-8057-2505)
- Mary E. Dickinson (ORCID: https://orcid.org/0000-0003-4372-9638)
- Duc Minh Duong (ORCID: https://orcid.org/0000-0001-5880-1888)
- Suyang Bao (ORCID: https://orcid.org/0000-0002-0435-5322)
- Alexandra R Garza (ORCID: https://orcid.org/0000-0003-3288-4237)
- David A. Bennett
- Joshua M. Shulman
Institutions
- Rush University Medical Center (US)
- Emory University (US)
- Baylor College of Medicine (US)
- Baylor School (US)
- Woodruff Health Sciences Center (US)
- Neurological Research Institute (US)
- Texas Children's Hospital (US)
- Baylor Genetics (US)
- Columbia University (US)
Publication Details
- Journal
- Human Molecular Genetics
- Published
- 2024-08-15
- DOI
- https://doi.org/10.1093/hmg/ddae115
- Citations
- 9
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 2.94
Funders
- Burroughs Wellcome Fund
- National Institutes of Health
- Eunice Kennedy Shriver National Institute of Child Health and Human Development