Brain insulin resistance accelerates Aβ fibrillogenesis by inducing GM1 ganglioside clustering in the presynaptic membranes

Naoki Yamamoto, Teruhiko Matsubara, Kazuya Sobue, Mamoru Tanida, Rika Kasahara, Kaori Naruse, Hideo Taniura, Toshinori Sato, Kenji Suzuki

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Type 2 diabetes mellitus is thought to be a significant risk factor for Alzheimer's disease. Insulin resistance also affects the central nervous system by regulating key processes, such as neuronal survival and longevity, learning and memory. However, the mechanisms underlying these effects remain uncertain. To investigate whether insulin resistance is associated with the assembly of amyloid β-protein (Aβ) at the cell surface of neurons, we inhibited insulin-signalling pathways of primary neurons. The treatments of insulin receptor (IR)-knockdown and a phosphatidylinositol 3-kinase inhibitor (LY294002), but not an extracellular signal-regulated kinase inhibitor, induced an increase in GM1 ganglioside (GM1) levels in detergent-resistant membrane microdomains of the neurons. The aged db/db mouse brain exhibited reduction in IR expression and phosphorylation of Akt, which later induced an increase in the high-density GM1-clusters on synaptosomes. Neurons treated with IR knockdown or LY294002, and synaptosomes of the aged db/db mouse brains markedly accelerated an assembly of Aβs.These results suggest that ageing and peripheral insulin resistance induce brain insulin resistance, which accelerates the assembly of Aβs by increasing and clustering of GM1 in detergent-resistant membrane microdomains of neuronal membranes.

Original languageEnglish
Pages (from-to)619-628
Number of pages10
JournalJournal of Neurochemistry
Volume121
Issue number4
DOIs
Publication statusPublished - 2012 May 1

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Keywords

  • Alzheimer
  • Amyloid β-protein
  • Diabetes
  • GM1 ganglioside
  • Insulin

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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