Alzheimer's Disease Risk Gene CD2AP Is a Dose-Sensitive Determinant of Synaptic Structure and Plasticity

Authors

Matea Pavešković
Ruth B De-Paula
Shamsideen A Ojelade
Evelyne K Tantry
Mikhail Y Kochukov
Suyang Bao
Surabi Veeraragavan
Alexandra R Garza
Snigdha Srivastava
Si-Yuan Song
Masashi Fujita
Duc M Duong
David A Bennett
Philip L De Jager
Nicholas T Seyfried
Mary E Dickinson
Jason D Heaney
Benjamin R Arenkiel
Joshua M Shulman

Publication Date

10-7-2024

Journal

Human Molecular Genetics

DOI

10.1093/hmg/ddae115

PMID

39146503

PMCID

PMC11458016

PubMedCentral® Posted Date

8-16-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Alzheimer Disease, Neuronal Plasticity, Mice, Synapses, Adaptor Proteins, Signal Transducing, Cytoskeletal Proteins, Mice, Knockout, Hippocampus, Humans, Neurons, Disease Models, Animal, Genetic Predisposition to Disease, Male, Brain, Alzheimer’s disease, synapse, CD2AP, proteomics, proteostasis, plasticity, haploinsufficiency, endocytosis, apolipoproteins, lipid metabolism

Abstract

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.

Comments

Associated Data