M1 muscarinic Agonists target major hallmarks of Alzheimer's disease the pivotal role of brain M1 receptors

被引：66
作者：
Fisher, Abraham [1 ]
机构：
[1] Israel Inst Biol Res, IL-74100 Ness Ziona, Israel
来源：
NEURODEGENERATIVE DISEASES | 2008年 / 5卷 / 3-4期
关键词：
M1 muscarinic receptor; beta-amyloid; tau pathology; cognition; ADAM17; protein kinase C; glycogen synthase; kinase; 3; beta; CEREBROSPINAL-FLUID LEVELS; TAU-PHOSPHORYLATION; BETA; PATHOLOGY; NEURONS; MICE; INHIBITION; ACTIVATION; CELLS;
D O I：
10.1159/000113712
中图分类号：
R74 [神经病学与精神病学];
学科分类号：
摘要：
M1 muscarinic receptor (M1 mAChR) is a therapeutic target in Alzheimer's disease (AD) and the M1-selective muscarinic agonists AF102B, AF150(S) and AF267B are cognitive enhancers and potential disease modifiers. Notably, AF267B decreased cerebrospinal fluid P-amyloid (A beta(40) and A beta(42)) in rabbits, decreased brain A beta levels in hypercholesterolemic rabbits and vascular A beta(42) deposition from the cortex in cholinotoxin-treated rabbits. In triple transgenic AD mice, AF267B reduced cognitive deficits and decreased A beta(42) and tau pathologies in the cortex and hippocampus (not amygdala), via M-1 mAChR activation of protein kinase C and a disintegrin and metalloproteinase domain 17 (ADAM17 or TACE) and decreased P-site amyloid precursor protein-cleaving enzyme I and glycogen synthase kinase 3 beta, respectively. AF267B is the first reported low-molecular-weight therapy that targets the major AD hallmarks. Copyright (c) 2008 S. Karger AG, Basel.
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收藏
页码：237 / 240
页数：4
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