title: High Fat Diet Enhances β-Site Cleavage of Amyloid Precursor Protein (APP) via Promoting β-Site APP Cleaving Enzyme 1/Adaptor Protein 2/Clathrin Complex Formation.
abstract: Obesity and type 2 diabetes are risk factors of Alzheimer's disease (AD). We reported that a high fat diet (HFD) promotes amyloid precursor protein (APP) cleavage by β-site APP cleaving enzyme 1 (BACE1) without increasing BACE1 levels in APP transgenic mice. However, the detailed mechanism had remained unclear. Here we demonstrate that HFD promotes BACE1/Adaptor protein-2 (AP-2)/clathrin complex formation by increasing AP-2 levels in APP transgenic mice. In Swedish APP overexpressing Chinese hamster ovary (CHO) cells as well as in SH-SY5Y cells, overexpression of AP-2 promoted the formation of BACE1/AP-2/clathrin complex, increasing the level of the soluble form of APP β (sAPPβ). On the other hand, mutant D495R BACE1, which inhibits formation of this trimeric complex, was shown to decrease the level of sAPPβ. Overexpression of AP-2 promoted the internalization of BACE1 from the cell surface, thus reducing the cell surface BACE1 level. As such, we concluded that HFD may induce the formation of the BACE1/AP-2/clathrin complex, which is followed by its transport of BACE1 from the cell surface to the intracellular compartments. These events might be associated with the enhancement of β-site cleavage of APP in APP transgenic mice. Here we present evidence that HFD, by regulation of subcellular trafficking of BACE1, promotes APP cleavage.
authors.affiliation: Department of Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Maesako
authors.affiliation: Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Uemura
authors.affiliation: SK project Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Tashiro
authors.affiliation: Department of Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Sasaki
authors.affiliation: Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Kiwamu
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Department of Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Yasuha
authors.initials: Y
authors.lastname: Noda
authors.affiliation: Department of Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Karin
authors.initials: K
authors.lastname: Ueda
authors.affiliation: Department of Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Asada-Utsugi
authors.affiliation: Department of Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kubota
authors.affiliation: Kyowa Hakko Kirin Co., Ltd, Shizuoka, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Okawa
authors.affiliation: Department of Neurology, National Cerebral and Cardiovascular Center, Osaka, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ihara
authors.affiliation: Department of Neurology, Sapporo Medical University, Sapporo, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Shimohama
authors.affiliation: Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Ishiki Hospital, Kagoshima, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Uemura
authors.affiliation: Department of Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Ayae
authors.initials: A
authors.lastname: Kinoshita
mesh_terms: D033962:Adaptor Protein Complex 2 / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019943:Amino Acid Substitution; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D059748:Proteolysis / Q000187:drug effects*
chemical_list: C545487:APP protein, human; D033962:Adaptor Protein Complex 2; D016564:Amyloid beta-Protein Precursor; D004041:Dietary Fats; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse