Alzheimer-Like Changes in Rat Models of Spontaneous Diabetes

  1. Zhen-guo Li1,
  2. Weixian Zhang1 and
  3. Anders A.F. Sima12
  1. 1Department of Pathology, Wayne State University, School of Medicine, Detroit, Michigan
  2. 2Department of Neurology, Wayne State University, School of Medicine, Detroit, Michigan
  1. 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

Abstract

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), β-secretase, β-amyloid, COOH-terminal fragment (CTF), insulin receptor, IGF-1 receptor, glycogen synthase kinase 3-β (GSK-3β), protein kinase B (Akt), phosphorylated τ (phospho-τ), 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, β-secretase, β-amyloid, and CTF were significantly increased in type 2 diabetic rats, as was phospho-τ. The insulin receptor expression was decreased in type 1 diabetes, whereas IGF-1 receptor was decreased in both models, as were Akt and GSK-3β expression.

CONCLUSIONS—The data show that β-amyloid and phospho-τ 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.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 24 April 2007. DOI: 10.2337/db07-0171.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted April 12, 2007.
    • Received February 6, 2007.
| Table of Contents

This Article

  1. Diabetes vol. 56 no. 7 1817-1824
  1. All Versions of this Article:
    1. db07-0171v1
    2. 56/7/1817 most recent