Abstract 19695: Possible Mutual Interaction Between Diabetes Mellitus and Alzheimer Disease: Generation of Novel Transgenic Mice Models of Alzheimer Disease With Diabetes
(Background) Recent epidemiological studies suggest that diabetes mellitus is a risk factor for Alzheimer disease. However, the underlying mechanisms for this association remain unknown. In this study, to better understand the pathophysiological interaction between these diseases, we generated novel animal models which reflect the pathologic conditions of both diseases and analyzed their metabolic and Alzheimer-like pathology.
(Methods) We crossed Alzheimer APP transgenic mice (APP23) with two types of diabetic mice (ob/ob and NSY mice), and established novel diabetic Alzheimer mouse models. We examined metabolic phenotypes (body weight, blood glucose and plasma insulin levels, glucose tolerance test and insulin tolerance test) and AD-like phenotypes (cognitive function: Morris water maze, brain amyloid burden and other neuropathologies) of these animals. In some studies, mice were fed high-fat diet to induce more severe diabetic phenotypes.
(Results) The onset of diabetic symptoms exacerbated Alzheimer-like cognitive dysfunction without increasing brain amyloid-beta burden. Notably, these cross-bred mice showed cerebrovascular inflammation, severe amyloid angiopathy, and impaired brain insulin signaling. On the other hand, the cross-bred mice showed more prominent diabetic phenotypes compared with original diabetic mice. We observed a significant positive correlation between brain amyloid-beta burden and severity of glucose intolerance, suggesting that amyloid pathology could aggravate diabetic conditions. In these cross-bred mice, insulin sensitivity of peripheral organs (liver and skeletal muscles) was significantly decreased.
(Conclusions) Here, we created novel diabetic Alzheimer mouse models with early onset of cognitive dysfunction. Cerebrovascular changes and alteration in brain insulin signaling might play a pivotal role in this relationship. Our findings suggest the presence of mutual interaction between Alzheimer disease and diabetes, and may reveal novel insights into this intensely debated pathological association.
- © 2010 by American Heart Association, Inc.