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

TY - JOUR

T1 - Swedish Alzheimer mutation induces mitochondrial dysfunction mediated by HSP60 mislocalization of amyloid precursor protein (APP) and beta-amyloid

AU - Walls, Ken Carlson

AU - Coskun, Pinar

AU - Gallegos-Perez, Jose Luis

AU - Zadourian, Nineli

AU - Freude, Karla Kristine

AU - Rasool, Suhail

AU - Blurton-Jones, Mathew

AU - Green, Kim Nicholas

AU - LaFerla, Frank Michael

PY - 2012/8/31

Y1 - 2012/8/31

N2 - 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.

AB - 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.

KW - Alzheimer Disease

KW - Amyloid

KW - Amyloid Precursor Protein Secretases

KW - Amyloid beta-Protein Precursor

KW - Animals

KW - Brain

KW - Cell Line

KW - Chaperonin 60

KW - Disease Models, Animal

KW - Humans

KW - Mice

KW - Mice, Transgenic

KW - Mitochondria

KW - Mitochondrial Proteins

KW - Protein Transport

U2 - 10.1074/jbc.M112.365890

DO - 10.1074/jbc.M112.365890

M3 - Journal article

C2 - 22753410

SN - 0021-9258

VL - 287

SP - 30317

EP - 30327

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 36

ER -