Tesseur Ina, Zou Kun, Esposito Luke, Bard Frederique, Berber Elisabeth, Can Judith Van, Lin Amy H, Crews Leslie, Tremblay Patrick, Mathews Paul, Mucke Lennart, Masliah Eliezer, Wyss-Coray Tony
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.
J Clin Invest. 2006 Nov;116(11):3060-9. doi: 10.1172/JCI27341.
Alzheimer's disease (AD) is characterized by progressive neurodegeneration and cerebral accumulation of the beta-amyloid peptide (Abeta), but it is unknown what makes neurons susceptible to degeneration. We report that the TGF-beta type II receptor (TbetaRII) is mainly expressed by neurons, and that TbetaRII levels are reduced in human AD brain and correlate with pathological hallmarks of the disease. Reducing neuronal TGF-beta signaling in mice resulted in age-dependent neurodegeneration and promoted Abeta accumulation and dendritic loss in a mouse model of AD. In cultured cells, reduced TGF-beta signaling caused neuronal degeneration and resulted in increased levels of secreted Abeta and beta-secretase-cleaved soluble amyloid precursor protein. These results show that reduced neuronal TGF-beta signaling increases age-dependent neurodegeneration and AD-like disease in vivo. Increasing neuronal TGF-beta signaling may thus reduce neurodegeneration and be beneficial in AD.
阿尔茨海默病（AD）的特征是进行性神经退行性变以及β-淀粉样肽（Aβ）在大脑中的积累，但尚不清楚是什么使神经元易发生变性。我们报告，转化生长因子-βⅡ型受体（TβRII）主要由神经元表达，并且在人类AD大脑中TβRII水平降低，且与该疾病的病理特征相关。在小鼠中降低神经元转化生长因子-β信号传导导致年龄依赖性神经退行性变，并在AD小鼠模型中促进Aβ积累和树突丢失。在培养细胞中，降低的转化生长因子-β信号传导导致神经元变性，并导致分泌的Aβ和β-分泌酶切割的可溶性淀粉样前体蛋白水平升高。这些结果表明，降低的神经元转化生长因子-β信号传导会增加体内年龄依赖性神经退行性变和AD样疾病。因此，增加神经元转化生长因子-β信号传导可能会减少神经退行性变，并对AD有益。
