期刊
NEUROBIOLOGY OF AGING
卷 23, 期 6, 页码 1039-1042出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/S0197-4580(02)00121-5
关键词
neurodegenerative diseases; A beta; brain amyloidosis; drug discovery
Extracellular senile plaques (SPs) are hallmark brain lesions of sporadic Alzheimer's disease (AD) and the likely consequence of genetic mutations that cause familial AD by increasing production of amyloidogenic amyloid-beta (Abeta). Although Abeta vaccines and inhibitors of amyloidogenic secretases are potential AD therapies, multifaceted strategies may be needed to effectively interrupt Abeta amyloidosis and prevent/arrest AD. One such strategy is the inhibition of Abeta fibrillization as a potential therapy for AD. Certain amyloid-binding molecules, such as Congo red (CR) and chrysamine G (CG) and Thioflavin S (TS) have been shown to bind SPs with high affinity and they can also arrest the formation of Abeta fibrils; however, CR, CG and TS are unsuitable for AD therapy because they do not cross the blood brain barrier (BBB). Therefore, we have generated novel CG and TS derivatives that specifically recognize fibrillar Abeta in vitro, arrest the formation of Abeta fibrils, and cross the BBB of transgenic (TG) mice that model AD amyloidosis. As proof of their ability to cross the BBB and of their high specificity for Abeta fibrils in vivo, we show that following intravenous injection in TG mice these compounds specifically label AD-like brain deposits of fibrillar Abeta. Furthermore, we demonstrate that CG derivative IMSB binds to SPs comprised of Abeta40 with much higher affinity than Abeta42 whereas TS derivative TDZM shows the opposite affinity. Moreover, IMSB but not TDZM binds selectively to neurofibrillary tangles. Significantly both IMSB and TDZM inhibit Abeta fibrillization in test tubes and in cultured cells. Thus, small amyloid binding molecules such as IMSB and TDZM which cross the BBB are potential therapeutic agents for the treatment of AD. (C) 2002 Elsevier Science Inc. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据