Swedish Alzheimer Mutation Induces Mitochondrial Dysfunction Mediated by HSP60 Mislocalization of Amyloid Precursor Protein (APP) and Beta-amyloid

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2012 Jul 4

PMID 22753410

Citations 44

Authors

Ken Carlson Walls

Pinar Coskun

Jose Luis Gallegos-Perez

Nineli Zadourian

Kristine Freude

Suhail Rasool

Mathew Blurton-Jones

Kim Nicholas Green

Frank Michael LaFerla

Affiliations

Soon will be listed here.

Abstract

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 Aβ and critical components of the γ-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 Aβ 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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