title: Brain insulin resistance accelerates Aβ fibrillogenesis by inducing GM1 ganglioside clustering in the presynaptic membranes.
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.
authors.affiliation: Laboratory of Neurochemistry, Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan. naokisan@ph.ritsumei.ac.jp
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Matsubara
authors.forename: Kazuya
authors.initials: K
authors.lastname: Sobue
authors.forename: Mamoru
authors.initials: M
authors.lastname: Tanida
authors.forename: Rika
authors.initials: R
authors.lastname: Kasahara
authors.forename: Kaori
authors.initials: K
authors.lastname: Naruse
authors.forename: Hideo
authors.initials: H
authors.lastname: Taniura
authors.forename: Toshinori
authors.initials: T
authors.lastname: Sato
authors.forename: Kenji
authors.initials: K
authors.lastname: Suzuki
mesh_terms: D000375:Aging / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D001923:Brain Chemistry / Q000502:physiology*; D002469:Cell Separation; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes; D005677:G(M1) Ganglioside / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009454:Neurofibrils / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000235:genetics / Q000502:physiology; D017661:Receptors, Presynaptic / Q000378:metabolism*; D013109:Sphingomyelins / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002867:Chromones; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D009025:Morpholines; D034741:RNA, Small Interfering; D017661:Receptors, Presynaptic; D013109:Sphingomyelins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D005677:G(M1) Ganglioside; D002784:Cholesterol; D011972:Receptor, Insulin