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

PLoS One. 2015 Sep 28;10(9):e0131199. doi: 10.1371/journal.pone.0131199. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Protein Complex 2 / genetics
  • Adaptor Protein Complex 2 / metabolism*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amino Acid Substitution
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Aspartic Acid Endopeptidases / genetics
  • Aspartic Acid Endopeptidases / metabolism*
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Dietary Fats / adverse effects
  • Dietary Fats / pharmacology*
  • Humans
  • Mice
  • Mice, Transgenic
  • Mutation, Missense
  • Obesity / genetics
  • Obesity / metabolism
  • Obesity / pathology
  • Protein Transport / drug effects
  • Protein Transport / genetics
  • Proteolysis / drug effects*

Substances

  • APP protein, human
  • Adaptor Protein Complex 2
  • Amyloid beta-Protein Precursor
  • Dietary Fats
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse

Grant support

AK, K. Uemura and MM are funded with Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan (AK: 24111524, K. Uemura: 23591243, MM: 13J00221, URL: http://www.mext.go.jp/a_menu/shinkou/hojyo/main5_a5.htm). MM is funded with Japan Society for the Promotion of Science research fellowship (820130600001, URL: http://www.jsps.go.jp/). Kyowa Hakko Kirin Co., Ltd provided support in the form of salary for author KO, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the ‘author contributions’ section.