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Published online April 24, 2007
Diabetes 56:1817-1824, 2007
DOI: 10.2337/db07-0171
© 2007 by the American Diabetes Association
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Alzheimer-Like Changes in Rat Models of Spontaneous Diabetes

Zhen-guo Li1, Weixian Zhang1, and Anders A.F. Sima1,2

1 Department of Pathology, Wayne State University, School of Medicine, Detroit, Michigan
2 Department of Neurology, Wayne State University, School of Medicine, Detroit, Michigan

Address correspondence and reprint requests to Dr. Anders A.F. Sima, Department of Pathology, Wayne State University, School of Medicine, 540 E. Canfield Ave., Detroit, MI 48201. E-mail: asima{at}med.wayne.edu

Abbreviations: APP, amyloid precursor protein; CNS, central nervous system; CTF, COOH-terminal fragment; GFAP, glial fibrillary acid protein; GSK-3ß, glycogen synthase kinase 3-ß

OBJECTIVE—To examine whether changes characteristic of Alzheimer's disease occur in two rat models with spontaneous onset of type 1 and type 2 diabetes.

RESEARCH DESIGN AND METHODS—The frontal cortices of 8-month-diabetic rats were examined with respect to neuronal densities, neurite degeneration, expression, and/or immunolocalization of amyloid precursor protein (APP), ß-secretase, ß-amyloid, COOH-terminal fragment (CTF), insulin receptor, IGF-1 receptor, glycogen synthase kinase 3-ß (GSK-3ß), protein kinase B (Akt), phosphorylated {tau} (phospho-{tau}), synaptophysin, and phosphorylated neurofilaments (SMI-31).

RESULTS—Neuronal loss occurred in both models, significantly more so in type 2 diabetic BBZDR/Wor rats compared with type 1 diabetic BB/Wor rats and was associated with a ninefold increase of dystrophic neurites. APP, ß-secretase, ß-amyloid, and CTF were significantly increased in type 2 diabetic rats, as was phospho-{tau}. The insulin receptor expression was decreased in type 1 diabetes, whereas IGF-1 receptor was decreased in both models, as were Akt and GSK-3ß expression.

CONCLUSIONS—The data show that ß-amyloid and phospho-{tau} accumulation occur in experimental diabetes and that this is associated with neurite degeneration and neuronal loss. The changes were more severe in the type 2 diabetic model and appear to be associated with insulin resistance and possibly hypercholesterolemia. The two models will provide useful tools to unravel further mechanistic associations between diabetes and Alzheimer's disease.


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