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Swedish Alzheimer mutation induces mitochondrial dysfunction mediated by HSP60 mislocalization of amyloid precursor protein (APP) and beta-amyloid.

Authors: Walls, KC  Coskun, P  Gallegos-Perez, JL  Zadourian, N  Freude, K  Rasool, S  Blurton-Jones, M  Green, KN  LaFerla, FM 
Citation: Walls KC, etal., J Biol Chem. 2012 Aug 31;287(36):30317-27. doi: 10.1074/jbc.M112.365890. Epub 2012 Jun 29.
Pubmed: (View Article at PubMed) PMID:22753410
DOI: Full-text: DOI:10.1074/jbc.M112.365890

Alzheimer disease (AD) is a complex disorder that involves numerous cellular and subcellular alterations including impairments in mitochondrial homeostasis. To better understand the role of mitochondrial dysfunction in the pathogenesis of AD, we analyzed brains from clinically well-characterized human subjects and from the 3xTg-AD mouse model of AD. We find Abeta and critical components of the gamma-secretase complex, presenilin-1, -2, and nicastrin, accumulate in the mitochondria. We used a proteomics approach to identify binding partners and show that heat shock protein 60 (HSP60), a molecular chaperone localized to mitochondria and the plasma membrane, specifically associates with APP. We next generated stable neural cell lines expressing human wild-type or Swedish APP, and provide corroborating in vitro evidence that HSP60 mediates translocation of APP to the mitochondria. Viral-mediated shRNA knockdown of HSP60 attenuates APP and Abeta mislocalization to the mitochondria. Our findings identify a novel interaction between APP and HSP60, which accounts for its translocation to the mitochondria.

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CRRD Object Information
CRRD ID: 10402831
Created: 2015-11-02
Species: All species
Last Modified: 2015-11-02
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.