Glucocorticoids increase amyloid-β and tau pathology in a mouse model of Alzheimer's disease
Glucocorticoids increase amyloid-β and tau pathology in a mouse model of Alzheimer's disease
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DOI：
10.1523/jneurosci.2797-06.2006
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发表时间：
2006-08-30
影响因子：
5.3
通讯作者：
LaFerla, Frank M.
中科院分区：
文献类型：
--
作者：
Green, Kim N.;Billings, Lauren M.;LaFerla, Frank M.
各种环境和遗传因素影响阿尔茨海默病（AD）的发生和进展。控制糖皮质激素循环水平的下丘脑-垂体-肾上腺（HPA）轴的失调发生在AD早期，导致皮质醇水平升高。HPA轴的紊乱与记忆障碍有关，并可能导致AD患者的认知能力下降，尽管尚不清楚这种影响是否涉及淀粉样蛋白β肽（A β）和tau蛋白的调节。通过体外和体内实验，我们报告了应激水平的糖皮质激素通过增加淀粉样蛋白前体蛋白（APP）和β -APP切割酶的稳态水平来增加A β的形成。此外，糖皮质激素增加tau积累，表明这种激素也加速神经原纤维缠结的发展。这些发现表明，在阿尔茨海默病中发现的高水平糖皮质激素不仅是疾病过程的结果，而且在阿尔茨海默病的发生和进展中起着核心作用。
Various environmental and genetic factors influence the onset and progression of Alzheimer's disease (AD). Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which controls circulating levels of glucocorticoid hormones, occurs early in AD, resulting in increased cortisol levels. Disturbances of the HPA axis have been associated with memory impairments and may contribute to the cognitive decline that occurs in AD, although it is unknown whether such effects involve modulation of the amyloid beta-peptide (A beta) and tau. Using in vitro and in vivo experiments, we report that stress-level glucocorticoid administration increases A beta formation by increasing steady-state levels of amyloid precursor protein (APP) and beta-APP cleaving enzyme. Additionally, glucocorticoids augment tau accumulation, indicating that this hormone also accelerates the development of neurofibrillary tangles. These findings suggest that high levels of glucocorticoids, found in AD, are not merely a consequence of the disease process but rather play a central role in the development and progression of AD.