Diet‐induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease

• Published in: The FASEB journal 2004-05, Vol.18 (7), p.902-904
• Main Authors: Ho, Lap, Qin, Weiping, Pompl, Patrick N., Xiang, Zhongmin, Wang, Jun, Zhao, Zhong, Peng, Yuanzhen, Cambareri, Gina, Rocher, Anne, Mobbs, Charles V., Hof, Patrick R., Pasinetti, Giulio Maria
• Format: Article
• Language: English
• Subjects: Alzheimer Disease; Amyloid beta-Peptides - biosynthesis; Amyloid beta-Protein Precursor - genetics; Amyloid Precursor Protein Secretases; Amyloidosis - etiology; Amyloidosis - genetics; Animals; Aspartic Acid Endopeptidases; Brain - metabolism; Brain - pathology; Cyclic AMP-Dependent Protein Kinase Type II; Cyclic AMP-Dependent Protein Kinases - metabolism; diabetes; Dietary Fats - toxicity; Disease Models, Animal; Endopeptidases - metabolism; Female; glycogen synthase kinase; Glycogen Synthase Kinase 3 - metabolism; Humans; Insulin Resistance; insulin‐degrading enzyme; Insulysin - deficiency; Insulysin - metabolism; Maze Learning; Mice; Mice, Transgenic; Nerve Tissue Proteins - metabolism; Peptide Fragments - biosynthesis; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Plaque, Amyloid; Protein Processing, Post-Translational; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Receptor, Insulin - physiology; Signal Transduction; Spatial Behavior; β‐amyloid
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.03-0978fje

ABSTRACT Recent epidemiological evidence indicates that insulin resistance, a proximal cause of Type II diabetes [a non‐insulin dependent form of diabetes mellitus (NIDDM)], is associated with an increased relative risk for Alzheimer's disease (AD). In this study we examined the role of dietary conditions leading to NIDDM‐like insulin resistance on amyloidosis in Tg2576 mice, which model AD‐like neuropathology. We found that diet‐induced insulin resistance promoted amyloidogenic β‐amyloid (Aβ) Aβ1–40 and Aβ1–42 peptide generation in the brain that corresponded with increased γ‐secretase activities and decreased insulin degrading enzyme (IDE) activities. Moreover, increased Aβ production also coincided with increased AD‐type amyloid plaque burden in the brain and impaired performance in a spatial water maze task. Further exploration of the apparent interrelationship of insulin resistance to brain amyloidosis revealed a functional decrease in insulin receptor (IR)‐mediated signal transduction in the brain, as suggested by decreased IR β‐subunit (IRβ) Y1162/1163 autophosphorylation and reduced phosphatidylinositol 3 (PI3)‐kinase/pS473‐AKT/Protein kinase (PK)‐B in these same brain regions. This latter finding is of particular interest given the known inhibitory role of AKT/PKB on glycogen synthase kinase (GSK)‐3α activity, which has previously been shown to promote Aβ peptide generation. Most interestingly, we found that decreased pS21‐GSK‐3α and pS9‐GSK‐ 3β phosphorylation, which is an index of GSK activation, positively correlated with the generation of brain C‐terminal fragment (CTF)‐γ cleavage product of amyloid precursor protein, an index of γ‐secretase activity, in the brain of insulin‐resistant relative to normoglycemic Tg2576 mice. Our study is consistent with the hypothesis that insulin resistance may be an underlying mechanism responsible for the observed increased relative risk for AD neuropathology, and presents the first evidence to suggest that IR signaling can influence Aβ production in the brain.