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The role of CD2AP in the Pathogenesis of Alzheimer's Disease.

ABSTRACT: Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by irreversible decline in cognition with unclear pathogenesis. Recently, accumulating evidence has revealed that CD2 associated protein (CD2AP), a scaffolding molecule regulates signal transduction and cytoskeletal molecules, is implicated in AD pathogenesis. Several single nucleotide polymorphisms (SNPs) in CD2AP gene are associated with higher risk for AD and mRNA levels of CD2AP are decreased in peripheral lymphocytes of sporadic AD patients. Furthermore, CD2AP loss of function is linked to enhanced A? production, Tau-induced neurotoxicity, abnormal neurite structure modulation and reduced blood-brain barrier integrity. This review is to summarize the recent discoveries about the genetics and known functions of CD2AP. The recent evidence concerning the roles of CD2AP in the AD pathogenesis is summarized and CD2AP can be a promising therapeutic target for AD.

SUBMITTER: Tao QQ

PROVIDER: S-EPMC6675523 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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The role of CD2AP in the Pathogenesis of Alzheimer's Disease.

Tao Qing-Qing QQ Chen Yu-Chao YC Wu Zhi-Ying ZY

Aging and disease 20190801 4

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by irreversible decline in cognition with unclear pathogenesis. Recently, accumulating evidence has revealed that CD2 associated protein (CD2AP), a scaffolding molecule regulates signal transduction and cytoskeletal molecules, is implicated in AD pathogenesis. Several single nucleotide polymorphisms (SNPs) in <i>CD2AP</i> gene are associated with higher risk for AD and mRNA levels of CD2AP are decreased in periph ...[more]

PMID: 31440393

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Project description:Genome-wide association studies have described several genes as genetic susceptibility loci for Alzheimer's disease (AD). Among them, CD2AP encodes CD2-associated protein, a scaffold protein implicated in dynamic actin remodeling and membrane trafficking during endocytosis and cytokinesis. Although a clear link between CD2AP defects and glomerular pathology has been described, little is known about the function of CD2AP in the brain. The aim of this study was to analyze the distribution of CD2AP in the AD brain and its potential associations with tau aggregation and β-amyloid (Aβ) deposition. First, we performed immunohistochemical analysis of CD2AP expression in brain tissue from AD patients and controls (N = 60). Our results showed granular CD2AP immunoreactivity in the human brain endothelium in all samples. In AD cases, no CD2AP was found to be associated with Aβ deposits in vessels or parenchymal plaques. CD2AP neuronal inclusions similar to neurofibrillary tangles (NFT) and neuropil thread-like deposits were found only in AD samples. Moreover, immunofluorescence analysis revealed that CD2AP colocalized with pTau. Regarding CD2AP neuronal distribution, a hierarchical progression from the entorhinal to the temporal and occipital cortex was detected. We found that CD2AP immunodetection in neurons was strongly and positively associated with Braak neurofibrillary stage, independent of age and other pathological hallmarks. To further investigate the association between pTau and CD2AP, we included samples from cases of primary tauopathies (corticobasal degeneration [CBD], progressive supranuclear palsy [PSP], and Pick's disease [PiD]) in our study. Among these cases, CD2AP positivity was only found in PiD samples as neurofibrillary tangle-like and Pick body-like deposits, whereas no neuronal CD2AP deposits were detected in PSP or CBD samples, which suggested an association of CD2AP neuronal expression with 3R-Tau-diseases. In conclusion, our findings open a new road to investigate the complex cellular mechanism underlying the tangle conformation and tau pathology in the brain.

Dataset Information

The role of CD2AP in the Pathogenesis of Alzheimer's Disease.

Publications

The role of CD2AP in the Pathogenesis of Alzheimer's Disease.

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