Buckingham Steven D, Jones Andrew K, Brown Laurence A, Sattelle David B
Medical Research Council Functional Genomics Unit, Department of Physiology Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK, OX1 3QX.
Pharmacol Rev. 2009 Mar;61(1):39-61. doi: 10.1124/pr.108.000562. Epub 2009 Mar 16.
Alzheimer's disease (AD), the major contributor to dementia in the elderly, involves accumulation in the brain of extracellular plaques containing the beta-amyloid protein (Abeta) and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. AD is also characterized by a loss of neurons, particularly those expressing nicotinic acetylcholine receptors (nAChRs), thereby leading to a reduction in nAChR numbers. The Abeta(1-42) protein, which is toxic to neurons, is critical to the onset and progression of AD. The discovery of new drug therapies for AD is likely to be accelerated by an improved understanding of the mechanisms whereby Abeta causes neuronal death. We examine the evidence for a role in Abeta(1-42) toxicity of nAChRs; paradoxically, nAChRs can also protect neurons when activated by nicotinic ligands. Abeta peptides and nicotine differentially activate several intracellular signaling pathways, including the phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog pathway, the extracellular signal-regulated kinase/mitogen-activated protein kinase, and JAK-2/STAT-3 pathways. These pathways control cell death or survival and the secretion of Abeta peptides. We propose that understanding the differential activation of these pathways by nicotine and/or Abeta(1-42) may offer the prospect of new routes to therapy for AD.
阿尔茨海默病（AD）是老年人痴呆的主要病因，其特征是大脑中出现含有β-淀粉样蛋白（Aβ）的细胞外斑块堆积以及过度磷酸化tau蛋白的细胞内神经原纤维缠结。AD的另一个特征是神经元丧失，尤其是那些表达烟碱型乙酰胆碱受体（nAChRs）的神经元，从而导致nAChR数量减少。对神经元有毒性的Aβ（1-42）蛋白对AD的发病和进展至关重要。对Aβ导致神经元死亡机制的深入了解可能会加速AD新药疗法的发现。我们研究了nAChRs在Aβ（1-42）毒性中作用的证据；矛盾的是，当被烟碱配体激活时，nAChRs也可以保护神经元。Aβ肽和尼古丁以不同方式激活多种细胞内信号通路，包括磷脂酰肌醇3激酶/v-akt小鼠胸腺瘤病毒癌基因同源物通路、细胞外信号调节激酶/丝裂原活化蛋白激酶以及JAK-2/STAT-3通路。这些通路控制细胞死亡或存活以及Aβ肽的分泌。我们认为，了解尼古丁和/或Aβ（1-42）对这些通路的不同激活作用可能为AD治疗提供新的途径。
