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Effects of CD2-associated protein deficiency on amyloid-? in neuroblastoma cells and in an APP transgenic mouse model.

ABSTRACT: CD2-associated protein (CD2AP) is an SH3-containing scaffold adaptor protein which regulates the actin cytoskeleton. Recently, CD2AP was identified as a genetic risk factor for Alzheimer's disease (AD) by several genome-wide association studies. One of the hallmarks of AD is the accumulation of aggregated forms of Amyloid-? (A?) in the brain. In humans, CD2AP AD susceptibility locus (rs9349407) is associated with an increased plaque burden. A? production is highly regulated by endocytosis and is influenced by lysosomal function. Lysosomal trafficking is influenced by CD2AP. In this study, we decreased CD2AP levels in N2a neuroblastoma cultures and PS1APP mice and analyzed A? levels and plaque burden.Our data show that suppressing CD2AP expression using shRNA in N2a-APP695 cells results in decreased cell membrane amyloid precursor protein, decreased A? release and a lower A?42/A?40 ratio. CD2AP protein is expressed in the brain as detected by western blot, and the expression level is dependent on gene dosage. In 1-month old PS1APP mice, complete loss of CD2AP in brain resulted in a decreased A?42/A?40 ratio in brain tissue lysates while there was no effect on A? deposition or accumulation in PS1APP mice expressing one copy of CD2AP.CD2-Associated Protein affects A? levels and A?42/A?40 ratio in vitro. The effect of CD2-Associated Protein on A? metabolism is subtle in vivo.

SUBMITTER: Liao F

PROVIDER: S-EPMC4374406 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Effects of CD2-associated protein deficiency on amyloid-β in neuroblastoma cells and in an APP transgenic mouse model.

Liao Fan F Jiang Hong H Srivatsan Subhashini S Xiao Qingli Q Lefton Katheryn B KB Yamada Kaoru K Mahan Thomas E TE Lee Jin-Moo JM Shaw Andrey S AS Holtzman David M DM

Molecular neurodegeneration 20150319

<h4>Background</h4>CD2-associated protein (CD2AP) is an SH3-containing scaffold adaptor protein which regulates the actin cytoskeleton. Recently, CD2AP was identified as a genetic risk factor for Alzheimer's disease (AD) by several genome-wide association studies. One of the hallmarks of AD is the accumulation of aggregated forms of Amyloid-β (Aβ) in the brain. In humans, CD2AP AD susceptibility locus (rs9349407) is associated with an increased plaque burden. Aβ production is highly regulated by ...[more]

PMID: 25887956

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Project description:BackgroundThe role of mitochondrial dysfunction has long been implicated in age-related brain pathology, including Alzheimer's disease (AD). However, the mechanism by which mitochondrial dysfunction may cause neurodegeneration in AD is unclear. To model mitochondrial dysfunction in vivo, we utilized mice that harbor a knockin mutation that inactivates the proofreading function of mitochondrial DNA polymerase ? (PolgA D257A), so that these mice accumulate mitochondrial DNA mutations with age. PolgA D257A mice develop a myriad of mitochondrial bioenergetic defects and physical phenotypes that mimic premature ageing, with subsequent death around one year of age.ResultsWe crossed the D257A mice with a well-established transgenic AD mouse model (APP/Ld) that develops amyloid plaques. We hypothesized that mitochondrial dysfunction would affect A? synthesis and/or clearance, thus contributing to amyloidogenesis and triggering neurodegeneration. Initially, we discovered that A?42 levels along with A?42 plaque density were increased in D257A; APP/Ld bigenic mice compared to APP/Ld monogenic mice. Elevated A? production was not responsible for increased amyloid pathology, as levels of BACE1, PS1, C99, and C83 were unchanged in D257A; APP/Ld compared to APP/Ld mice. However, the levels of a major A? clearance enzyme, insulin degrading enzyme (IDE), were reduced in mice with the D257A mutation, suggesting this as mechanism for increased amyloid load. In the presence of the APP transgene, D257A mice also exhibited significant brain atrophy with apparent cortical thinning but no frank neuron loss. D257A; APP/Ld mice had increased levels of 17 kDa cleaved caspase-3 and p25, both indicative of neurodegeneration. Moreover, D257A; APP/Ld neurons appeared morphologically disrupted, with swollen and vacuolated nuclei.ConclusionsOverall, our results implicate synergism between the effects of the PolgA D257A mutation and A? in causing neurodegeneration. These findings provide insight into mechanisms of mitochondrial dysfunction that may contribute to the pathogenesis of AD via decreased clearance of A?.

Dataset Information

Effects of CD2-associated protein deficiency on amyloid-? in neuroblastoma cells and in an APP transgenic mouse model.

Publications

Effects of CD2-associated protein deficiency on amyloid-β in neuroblastoma cells and in an APP transgenic mouse model.

Similar Datasets

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