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CD2-associated protein (CD2AP) overexpression accelerates amyloid precursor protein (APP) transfer from early endosomes to the lysosomal degradation pathway.

ABSTRACT: A hallmark of Alzheimer's disease (AD) pathology is the appearance of senile plaques, which are composed of ?-amyloid (A?) peptides. A? is produced by sequential cleavages of amyloid precursor protein (APP) by ?- and ?-secretases. These cleavages take place in endosomes during intracellular trafficking of APP through the endocytic and recycling pathways. Genome-wide association studies have identified several risk factors for late-onset AD, one of which is CD2-associated protein (CD2AP), an adaptor molecule that regulates membrane trafficking. Although CD2AP's involvement in APP trafficking has recently been reported, how APP trafficking is regulated remains unclear. We sought to address this question by investigating the effect of CD2AP overexpression or knockdown on the intracellular APP distribution and degradation of APP in cultured COS-7 and HEK293 cells. We found that overexpression of CD2AP increases the localization of APP to Rab7-positive late endosomes, and decreases its localization to Rab5-positive early endosomes. CD2AP overexpression accelerated the onset of APP degradation without affecting its degradation rate. Furthermore, nutrient starvation increased the localization of APP to Rab7-positive late endosomes, and CD2AP overexpression stimulated starvation-induced lysosomal APP degradation. Moreover, the effect of CD2AP on the degradation of APP was confirmed by CD2AP overexpression and knockdown in primary cortical neurons from mice. We conclude that CD2AP accelerates the transfer of APP from early to late endosomes. This transfer in localization stimulates APP degradation by reducing the amount of time before degradation initiation. Taken together, these results may explain why impaired CD2AP function is a risk factor for AD.

SUBMITTER: Furusawa K

PROVIDER: S-EPMC6635452 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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CD2-associated protein (CD2AP) overexpression accelerates amyloid precursor protein (APP) transfer from early endosomes to the lysosomal degradation pathway.

Furusawa Kotaro K Takasugi Toshiyuki T Chiu Yung-Wen YW Hori Yukiko Y Tomita Taisuke T Fukuda Mitsunori M Hisanaga Shin-Ichi SI

The Journal of biological chemistry 20190528 28

A hallmark of Alzheimer's disease (AD) pathology is the appearance of senile plaques, which are composed of β-amyloid (Aβ) peptides. Aβ is produced by sequential cleavages of amyloid precursor protein (APP) by β- and γ-secretases. These cleavages take place in endosomes during intracellular trafficking of APP through the endocytic and recycling pathways. Genome-wide association studies have identified several risk factors for late-onset AD, one of which is CD2-associated protein (CD2AP), an adap ...[more]

PMID: 31138646

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Project description:The Î²-amyloid precursor protein APP and the related APLPs, undergo complex proteolytic processing giving rise to several fragments. Whereas it is well established that AÎ² accumulation is a central trigger for Alzheimer disease (AD), the physiological role of APP family members and their diverse proteolytic products is still largely unknown. The secreted APPsÎ± ectodomain has been shown to be involved in neuroprotection and synaptic plasticity. The Î³-secretase generated APP intracellular domain AICD, functions as a transciptional regulator in heterologous reporter assays, although its role for endogenous gene regulation has remained controversial. To gain further insight into the molecular changes associated with knockout phenotypes and to elucidate the physiological functions of APP family members including their proposed role as transcriptional regulators we performed a DNA microarray transcriptome profiling of the frontal cortex of adult wild type, APP-/-, APLP2-/- and APPsÎ± knockin (KI) mice, APPÎ±/Î±, expressing solely the secreted APPsÎ± ectodomain. Biological pathways affected by the lack of APP family members included regulation of neurogenesis, regulation of transcription and regulation of neuron projection development. Comparative analysis of transcriptome changes and qPCR validation identified co-regulated gene sets. Interestingly, these included heat shock proteins and plasticity related genes that were down-regulated in knock-out cortices. In contrast, we failed to detect significant differences in expression of previously proposed AICD target genes including Bace1, Kai1, Gsk3b, p53, Tip60 and Vglut2. Only Egfr was slightly up-regulated in APLP2-/- mice. Comparison of APP-/- and APPÎ±/Î± with wild-type mice revealed a high proportion of co-regulated genes indicating an important role of the C-terminus for cellular signaling. Finally, comparison of APLP2-/- on different genetic backgrounds revealed that background related transcriptome changes may dominate over changes due to the knockout of a single gene. Shared transcriptome profiles corroborated closely related physiological functions of APP family members in the adult central nervous system. As expression of proposed AICD target genes was not altered in adult cortex, this may indicate that these genes are not affected by lack of APP under resting conditions or only in a small subset of cells. Prefrontal cortices of adult male mice (24 - 28 weeks) of the following genotypes were analyzed: WT (n=3), APP-/- (n=3), APPÎ±/Î± (n=3), APLP2-/- (n=3), APLP2(R1)-/- (n=3). WT, APP-/-, APPÎ±/Î±, APLP2-/- had been backcrossed for six generations to C57BL/6 mice. APLP2(R1)-/- harbors the identical knockout allele as APLP2-/- but was back-crossed only once.

Dataset Information

CD2-associated protein (CD2AP) overexpression accelerates amyloid precursor protein (APP) transfer from early endosomes to the lysosomal degradation pathway.

Publications

CD2-associated protein (CD2AP) overexpression accelerates amyloid precursor protein (APP) transfer from early endosomes to the lysosomal degradation pathway.

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