Type 1 diabetes exaggerates features of Alzheimer's disease in APP transgenic mice.
A number of studies suggest an association between Alzheimer's disease (AD) and diabetes: AD patients show impaired insulin function, whereas cognitive deficits and increased risk of developing AD occur in diabetic patients. The reasons for the increased risk are not known. Recent studies of disturbances in the insulin-signaling pathway have revealed new perspectives on the links between AD and Type 1 diabetes with a particular focus on glycogen synthase-kinase-3 (GSK3). We have therefore characterized a mouse model of combined insulin-deficient diabetes and AD and find that diabetes exaggerated defects in the brain of APP transgenic mice. Mice with combined APP overexpression and diabetes showed a decreased insulin receptor activity and an increased GSK3beta activity. Concomitantly, tau phosphorylation and number of Abeta plaques, the two pathologic hallmarks of AD, were increased in the brain of diabetic-APP transgenic mice. Our results indicate that the pathologic features of AD are exaggerated in the brain of APP transgenic mice that have concurrent insulin-deficient diabetes, and underscore a possible mechanism of brain dysfunction common to AD and diabetes.
Jolivalt
Corinne G
CG
Department of Pathology, University of California San Diego, La Jolla, CA 92093-0612, USA. cjolivalt@ucsd.edu
Hurford
Rosemarie
R
Lee
Corinne A
CA
Dumaop
Wilmar
W
Rockenstein
Edward
E
Masliah
Eliezer
E
D000544:Alzheimer Disease / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D003071:Cognition / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007339:Insulysin / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D011972:Receptor, Insulin / Q000378:metabolism; D012720:Severity of Illness Index; D016708:Synaptophysin / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D016708:Synaptophysin; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D011972:Receptor, Insulin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D007339:Insulysin