Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Abeta deposition in an Alzheimer mouse model with diabetes.

Abstract

Recent epidemiological studies suggest that diabetes mellitus is a strong risk factor for Alzheimer disease. However, the underlying mechanisms remain largely unknown. In this study, to investigate the pathophysiological interaction between these diseases, we generated animal models that reflect the pathologic conditions of both diseases. We crossed Alzheimer transgenic mice (APP23) with two types of diabetic mice (ob/ob and NSY mice), and analyzed their metabolic and brain pathology. The onset of diabetes exacerbated Alzheimer-like cognitive dysfunction without an increase in brain amyloid-beta burden in double-mutant (APP(+)-ob/ob) mice. Notably, APP(+)-ob/ob mice showed cerebrovascular inflammation and severe amyloid angiopathy. Conversely, the cross-bred mice showed an accelerated diabetic phenotype compared with ob/ob mice, suggesting that Alzheimer amyloid pathology could aggravate diabetes. Similarly, APP(+)-NSY fusion mice showed more severe glucose intolerance compared with diabetic NSY mice. Furthermore, high-fat diet feeding induced severe memory deficits in APP(+)-NSY mice without an increase in brain amyloid-beta load. Here, we created 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. These findings could provide insights into this intensely debated association.

• Authors: Shuko Takeda, Naoyuki Sato, Kozue Uchio-Yamada, Kyoko Sawada, Takanori Kunieda, Daisuke Takeuchi, Hitomi Kurinami, Mitsuru Shinohara, Hiromi Rakugi, Ryuichi Morishita
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 107 Issue 15 Pg. 7036-41 (Apr 13 2010) ISSN: 1091-6490 [Electronic] United States
• PMID: 20231468 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Insulin

Topics

• Alzheimer Disease (complications, physiopathology)
• Amyloid beta-Peptides (biosynthesis)
• Animal Feed
• Animals
• Cerebrovascular Circulation
• Crosses, Genetic
• Diabetes Mellitus, Experimental (physiopathology)
• Disease Models, Animal
• Female
• Inflammation
• Insulin (metabolism)
• Male
• Memory Disorders (complications, physiopathology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic