title: Swedish Alzheimer mutation induces mitochondrial dysfunction mediated by HSP60 mislocalization of amyloid precursor protein (APP) and beta-amyloid.
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.
authors: Department of Neurobiology and Behavior, University of California, Irvine, CA 92697-4545, USA. kwalls@uci.edu
authors: Ken Carlson
authors: KC
authors: Walls
authors: Pinar
authors: P
authors: Coskun
authors: Jose Luis
authors: JL
authors: Gallegos-Perez
authors: Nineli
authors: N
authors: Zadourian
authors: Kristine
authors: K
authors: Freude
authors: Suhail
authors: S
authors: Rasool
authors: Mathew
authors: M
authors: Blurton-Jones
authors: Kim Nicholas
authors: KN
authors: Green
authors: Frank Michael
authors: FM
authors: LaFerla
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000682:Amyloid / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D018834:Chaperonin 60 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics
chemical_list: C545487:APP protein, human; D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D018834:Chaperonin 60; C557066:Hspd1 protein, mouse; D024101:Mitochondrial Proteins; D053829:Amyloid Precursor Protein Secretases