Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease.
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.
Ho
Lap
L
Neuroinflammation Research Laboratories, Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA.
Qin
Weiping
W
Pompl
Patrick N
PN
Xiang
Zhongmin
Z
Wang
Jun
J
Zhao
Zhong
Z
Peng
Yuanzhen
Y
Cambareri
Gina
G
Rocher
Anne
A
Mobbs
Charles V
CV
Hof
Patrick R
PR
Pasinetti
Giulio Maria
GM
D000544:Alzheimer Disease; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000686:Amyloidosis / Q000209:etiology* / Q000235:genetics; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004041:Dietary Fats / Q000633:toxicity*; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000378:metabolism; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D007339:Insulysin / Q000172:deficiency / Q000378:metabolism; D018782:Maze Learning; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000096:biosynthesis*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D058225:Plaque, Amyloid; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin / Q000502:physiology; D015398:Signal Transduction; D013037:Spatial Behavior
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016282:Aspartic Acid Endopeptidases; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D004041:Dietary Fats; D010450:Endopeptidases; D038362:Glycogen Synthase Kinase 3; D007339:Insulysin; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C494918:AKT1 protein, human; C448021:glycogen synthase kinase 3 alpha; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse