Vandal Milene, White Phillip J, Chevrier Geneviève, Tremblay Cyntia, St-Amour Isabelle, Planel Emmanuel, Marette Andre, Calon Frederic
*Faculté de Pharmacie, Institut des Nutraceutiques et des Aliments Fonctionnels, and Département de Medicine, Axe de Cardiologie, Faculté de Médicine, Université Laval, Québec, Québec, Canada; Axe Neurosciences, Centre de Recherche du Centre Hospitalier de l'Université Laval (CHUL), Québec, Québec, Canada; Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, North Carolina, USA; and Institut Universitaire de Pneumologie et de Cardiologie, Québec, Québec, Canada.
FASEB J. 2015 Oct;29(10):4273-84. doi: 10.1096/fj.14-268482. Epub 2015 Jun 24.
Alzheimer's disease (AD) has been associated with type II diabetes (T2D) and obesity in several epidemiologic studies. To determine whether AD neuropathology can cause peripheral metabolic impairments, we investigated metabolic parameters in the triple-transgenic (3xTg)-AD mouse model of AD, compared with those in nontransgenic (non-Tg) controls, at 6, 8, and 14 mo of age. We found a more pronounced cortical Aβ accumulation (2- and 3.5-fold increase in Aβ42 in the soluble and insoluble protein fractions, respectively) in female 3xTg-AD mice than in the males. Furthermore, female 3xTg-AD mice displayed a significant deterioration in glucose tolerance (AUC, +118% vs. non-Tg mice at 14 mo). Fasting plasma insulin levels rose 2.5-fold from 6 to 14 mo of age in female 3xTg-AD mice. Glucose intolerance and cortical amyloid pathology worsened with age, and both were more pronounced in the females. Pancreatic amyloidopathy was revealed and could underlie the observed deficit in glycemic response in 3xTg-AD mice. The present results suggest that AD-like neuropathology extends to the pancreas in the 3xTg-AD mouse, leading to glucose intolerance and contributing to a pathologic self-amplifying loop between AD and T2D.
多项流行病学研究表明，阿尔茨海默病（AD）与2型糖尿病（T2D）和肥胖有关。为了确定AD神经病理学是否会导致外周代谢障碍，我们研究了三转基因（3xTg）-AD小鼠模型在6、8和14月龄时的代谢参数，并与非转基因（non-Tg）对照小鼠进行了比较。我们发现，雌性3xTg-AD小鼠的皮质Aβ积累更为明显（可溶性和不可溶性蛋白组分中的Aβ42分别增加了2倍和3.5倍）。此外，雌性3xTg-AD小鼠的糖耐量显著恶化（14月龄时的AUC与非Tg小鼠相比增加了118%）。雌性3xTg-AD小鼠的空腹血浆胰岛素水平在6至14月龄时上升了2.5倍。糖耐量异常和皮质淀粉样病变随年龄增长而恶化，且在雌性小鼠中更为明显。3xTg-AD小鼠出现胰腺淀粉样病变，这可能是观察到的血糖反应缺陷的基础。目前的结果表明，3xTg-AD小鼠中类似AD的神经病理学延伸至胰腺，导致糖耐量异常，并促成AD和T2D之间的病理性自我放大循环。
