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Diabetes Accelerated Memory Dysfunction via Cerebrovascular Inflammation and Aβ Deposition in Alzheimer Mouse Model with Diabetes

Takeda, Shuko and Sato, Naoyuki and Uchio-Yamada, Kozue and Sawada, Kyoko and Kunieda, Takanori and Takeuchi, Daisuke and Kurinami, Hitomi and Shinohara, Mitsuru and Rakugi, Hiromi and Morishita, Ryuichi and Staufenbiel, Matthias (2010) Diabetes Accelerated Memory Dysfunction via Cerebrovascular Inflammation and Aβ Deposition in Alzheimer Mouse Model with Diabetes. Proceedings of the National Academy of Sciences of the United States of America, 107 (15). pp. 7036-7041. ISSN 0027-8424

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 novel animal models which 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-β (Aβ) burden in double-mutant (APP+-ob/ob) mice. Notably, APP+-ob/ob mice showed cerebrovascular inflammation and severe amyloid angiopathy.
On the other hand, the cross-bred mice showed an accelerated diabetic phenotype as compared to ob/ob mice, suggesting that Alzheimer amyloid pathology could aggravate
diabetes. Similarly, APP+-NSY fusion mice showed more severe glucose intolerance as compared to diabetic NSY mice. Furthermore, high-fat diet feeding induced severe
memory deficits in APP+-NSY mice without an increase in brain Aβ load. Here, we created novel 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 novel insights into this intensely
debated association.

Item Type: Article
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Additional Information: Author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: β-amyloid; insulin
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/2509

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