期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：13
页码：4068-4073
DOI：10.1073/pnas.1423764112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceAlzheimer's disease (AD) is a growing public health problem, in part because there are no effective therapies. Major roadblocks to the treatment of AD are the lack of adequate diagnostic tools and the absence of viable therapeutic targets. It is now clear that AD is characterized by inflammation. Our results indicate that AD patients and mouse models have increased activation of a set of proteins known as the contact activation system in their circulation. We also demonstrate that the AD-related peptide A{beta} can initiate activation of this system in the circulation of animal models. Because the contact activation system contributes to inflammation, our results suggest new pathogenic mechanisms, diagnostic tests, and therapeutic targets for AD. Alzheimer's disease (AD) is characterized by accumulation of the {beta}-amyloid peptide (A{beta}), which likely contributes to disease via multiple mechanisms. Increasing evidence implicates inflammation in AD, the origins of which are not completely understood. We investigated whether circulating A{beta} could initiate inflammation in AD via the plasma contact activation system. This proteolytic cascade is triggered by the activation of the plasma protein factor XII (FXII) and leads to kallikrein-mediated cleavage of high molecular-weight kininogen (HK) and release of proinflammatory bradykinin. A{beta} has been shown to promote FXII-dependent cleavage of HK in vitro. In addition, increased cleavage of HK has been found in the cerebrospinal fluid of patients with AD. Here, we show increased activation of FXII, kallikrein activity, and HK cleavage in AD patient plasma. Increased contact system activation is also observed in AD mouse model plasma and in plasma from wild-type mice i.v. injected with A{beta}42. Our results demonstrate that A{beta}42-mediated contact system activation can occur in the AD circulation and suggest new pathogenic mechanisms, diagnostic tests, and therapies for AD.
关键词：Alzheimer’s disease ; factor XII ; high molecular-weight kininogen ; plasma kallikrein
