Lee Ju-Hyun, Lau Kwok-Fai, Perkinton Michael S, Standen Claire L, Shemilt Stephen J A, Mercken Luc, Cooper Jonathan D, McLoughlin Declan M, Miller Christopher C J
Department of Neuroscience and Section of Old Age Psychiatry, The Institute of Psychiatry, Kings College, De Crespigny Park, Denmark Hill, London SE5 8AF, U.K.
J Biol Chem. 2003 Nov 21;278(47):47025-9. doi: 10.1074/jbc.M300503200. Epub 2003 Sep 11.
Increased production and deposition of the 40-42-amino acid beta-amyloid peptide (Abeta) is believed to be central to the pathogenesis of Alzheimer's disease. Abeta is derived from the amyloid precursor protein (APP), but the mechanisms that regulate APP processing to produce Abeta are not fully understood. X11alpha (also known as munc-18-interacting protein-1 (Mint1)) is a neuronal adaptor protein that binds APP and modulates APP processing in transfected non-neuronal cells. To investigate the in vivo effect of X11alpha on Abeta production in the brain, we created transgenic mice that overexpress X11alpha and crossed these with transgenics harboring a familial Alzheimer's disease mutant APP that produces increased levels of Abeta (APPswe Tg2576 mice). Analyses of Abeta levels in the offspring generated from two separate X11alpha founder mice revealed a significant, approximate 20% decrease in Abeta(1-40) in double transgenic mice expressing APPswe/X11alpha compared with APPswe mice. At a key time point in Abeta plaque deposition (8 months old), the number of Abeta plaques was also deceased in APPswe/X11alpha mice. Thus, we report here the first demonstration that X11alpha inhibits Abeta production and deposition in vivo in the brain.
40 - 42个氨基酸的β-淀粉样肽（Aβ）产量增加和沉积被认为是阿尔茨海默病发病机制的核心。Aβ源自淀粉样前体蛋白（APP），但调节APP加工以产生Aβ的机制尚未完全明确。X11α（也称为与munc - 18相互作用蛋白1（Mint1））是一种神经元衔接蛋白，在转染的非神经元细胞中与APP结合并调节APP加工。为了研究X11α在体内对大脑中Aβ产生的影响，我们构建了过表达X11α的转基因小鼠，并将其与携带产生更高水平Aβ的家族性阿尔茨海默病突变APP的转基因小鼠（APPswe Tg2576小鼠）杂交。对来自两个独立的X11α奠基小鼠的后代中Aβ水平的分析显示，与APPswe小鼠相比，表达APPswe/X11α的双转基因小鼠中Aβ（1 - 40）显著降低了约20%。在Aβ斑块沉积的关键时间点（8个月大时），APPswe/X11α小鼠中的Aβ斑块数量也减少了。因此，我们在此首次证明X11α在体内可抑制大脑中Aβ的产生和沉积。
