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.

中文翻译：

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烟碱乙酰胆碱受体信号：在阿尔茨海默病和淀粉样蛋白神经保护中的作用。

阿尔茨海默病 (AD) 是老年人痴呆症的主要诱因，它涉及在大脑中积聚含有 β-淀粉样蛋白 (Abeta) 的细胞外斑块和过度磷酸化的 tau 蛋白的细胞内神经原纤维缠结。AD 的特征还在于神经元丢失，特别是那些表达烟碱型乙酰胆碱受体 (nAChR) 的神经元，从而导致 nAChR 数量减少。Abeta(1-42) 蛋白对神经元有毒，对 AD 的发病和进展至关重要。对 Abeta 导致神经元死亡的机制的更好理解可能会加速 AD 新药物疗法的发现。我们研究了在 nAChRs 的 Abeta(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。Abeta 肽和尼古丁差异激活几种细胞内信号通路，包括磷脂酰肌醇 3-激酶/v-akt 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和 JAK-2/STAT-3 通路. 这些途径控制细胞死亡或存活以及 Abeta 肽的分泌。我们建议了解尼古丁和/或 Abeta(1-42) 对这些途径的差异激活可能会为治疗 AD 的新途径提供前景。这些途径控制细胞死亡或存活以及 Abeta 肽的分泌。我们建议了解尼古丁和/或 Abeta(1-42) 对这些途径的差异激活可能会为治疗 AD 的新途径提供前景。这些途径控制细胞死亡或存活以及 Abeta 肽的分泌。我们建议了解尼古丁和/或 Abeta(1-42) 对这些途径的差异激活可能会为治疗 AD 的新途径提供前景。