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

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 beta-amyloid (Abeta) Abeta1-40 and Abeta1-42 peptide generation in the brain that corresponded with increased gamma-secretase activities and decreased insulin degrading enzyme (IDE) activities. Moreover, increased Abeta 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 beta-subunit (IRbeta) 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)-3alpha activity, which has previously been shown to promote Abeta peptide generation. Most interestingly, we found that decreased pS21-GSK-3alpha and pS9-GSK-3beta phosphorylation, which is an index of GSK activation, positively correlated with the generation of brain C-terminal fragment (CTF)-gamma cleavage product of amyloid precursor protein, an index of gamma-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 Abeta production in the brain.
Authors	Lap Ho, Weiping Qin, Patrick N Pompl, Zhongmin Xiang, Jun Wang, Zhong Zhao, Yuanzhen Peng, Gina Cambareri, Anne Rocher, Charles V Mobbs, Patrick R Hof, Giulio Maria Pasinetti
Journal	FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 18 Issue 7 Pg. 902-4 (May 2004) ISSN: 1530-6860 [Electronic] United States
PMID	15033922 (Publication Type: Journal Article)
Chemical References	Amyloid beta-Peptides Amyloid beta-Protein Precursor Dietary Fats Nerve Tissue Proteins Peptide Fragments Proto-Oncogene Proteins amyloid beta-protein (1-40) amyloid beta-protein (1-42) Receptor, Insulin AKT1 protein, human Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Cyclic AMP-Dependent Protein Kinase Type II Cyclic AMP-Dependent Protein Kinases Glycogen Synthase Kinase 3 glycogen synthase kinase 3 alpha Amyloid Precursor Protein Secretases Endopeptidases Aspartic Acid Endopeptidases BACE1 protein, human Bace1 protein, mouse Insulysin
Topics	Alzheimer Disease Amyloid Precursor Protein Secretases Amyloid beta-Peptides (biosynthesis) Amyloid beta-Protein Precursor (genetics) Amyloidosis (etiology, genetics) Animals Aspartic Acid Endopeptidases Brain (metabolism, pathology) Cyclic AMP-Dependent Protein Kinase Type II Cyclic AMP-Dependent Protein Kinases (metabolism) Dietary Fats (toxicity) Disease Models, Animal Endopeptidases (metabolism) Female Glycogen Synthase Kinase 3 (metabolism) Humans Insulin Resistance Insulysin (deficiency, 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

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