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The late‐onset Alzheimer's disease genetic risk factor CD2AP impacts synapses via actin dynamics
Author(s) -
Mirfakhar Farzaneh S.,
Almeida Claudia G.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.043900
Subject(s) - dendritic spine , microbiology and biotechnology , biology , endocytic cycle , synapse , actin , actin cytoskeleton , actin remodeling of neurons , cytoskeleton , mutant , neuroscience , cell , hippocampal formation , genetics , endocytosis , gene
Background In late‐onset Alzheimer’s disease (LOAD) the causal mechanisms of synaptic dysfunction that underlie the memory deficits that lead to dementia are not established. The search for genetic risk factors in LOAD led to the identification of more than 20 genes and three main mechanisms: endocytic trafficking, lipid metabolism and immune response. Here we aim to establish causality between a mutation in CD2AP, one of the endocytic trafficking risk factors, and synaptic dysfunction. Since CD2AP is a regulator of the actin cytoskeleton dynamics which is essential for spine morphology, we hypothesize that a LOAD mutation CD2AP may impact spines by deregulating actin. Method We have analyzed synapses and spines density as well as spinal actin in cortical mouse primary neurons either transiently overexpressing wild‐type and mutant CD2AP‐GFP as well as GFP as control or infected with lentivirus expressing GFP and shCD2AP or non‐targeting shRNA as control. Moreover, we investigated CD2AP synaptic localization by immunofluorescence microscopy. We used quantitative single‐cell analysis using ICY and Imaris software. Result We discovered that a pool of CD2AP is present in spines; and that both CD2AP wild‐type and mutant are significantly enriched in spines. Spines length decreased with larger spine heads, by CD2AP wild‐type and more pronouncedly by mutant CD2AP overexpression. Indicating that CD2AP might function at synapses, by regulating spine morphology. Indeed, synapses density was reduced by CD2AP knockdown. Mechanistically, we found that spinal F‐actin increased by CD2AP wild‐type and more pronouncedly by mutant CD2AP overexpression compared to control neurons. We are currently investigating whether spinal F‐actin is altered by CD2AP knockdown. Conclusion These results indicate that CD2AP regulates spine morphology and thus synapses. A LOAD mutant CD2AP may interfere with its function by dysregulating actin dynamics at spines. Overall CD2AP variants may contribute to LOAD development by directly interfering with synapses. References: (1) Ubelmann, Florent, et al. “Bin1 and CD2AP polarise the endocytic generation of beta‐amyloid.” EMBO reports 18.1 (2017): 102‐122. (2) Hollingworth, Paul, et al. “Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.” Nature genetics 43.5 (2011): 429.