Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Abeta deposition in an Alzheimer mouse model with diabetes.
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.
Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
Shuko
S
Takeda
Naoyuki
N
Sato
Kozue
K
Uchio-Yamada
Kyoko
K
Sawada
Takanori
T
Kunieda
Daisuke
D
Takeuchi
Hitomi
H
Kurinami
Mitsuru
M
Shinohara
Hiromi
H
Rakugi
Ryuichi
R
Morishita
D000544:Alzheimer Disease / Q000150:complications / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000821:Animal Feed; D000818:Animals; D002560:Cerebrovascular Circulation; D003433:Crosses, Genetic; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation; D007328:Insulin / Q000378:metabolism; D008297:Male; D008569:Memory Disorders / Q000150:complications / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
D016229:Amyloid beta-Peptides; D007328:Insulin