Boonen Rick A C M, van Tijn Paula, Zivkovic Danica
Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences & University Medical Centre Utrecht, Utrecht, The Netherlands.
Ageing Res Rev. 2009 Apr;8(2):71-82. doi: 10.1016/j.arr.2008.11.003. Epub 2008 Dec 3.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder, neuropathologically characterized by amyloid-beta (Abeta) plaques and hyperphosphorylated tau accumulation. AD occurs sporadically (SAD), or is caused by hereditary missense mutations in the amyloid precursor protein (APP) or presenilin-1 and -2 (PSEN1 and PSEN2) genes, leading to early-onset familial AD (FAD). Accumulating evidence points towards a role for altered Wnt/beta-catenin-dependent signaling in the etiology of both forms of AD. Presenilins are involved in modulating beta-catenin stability; therefore FAD-linked PSEN-mediated effects can deregulate the Wnt pathway. Genetic variations in the low-density lipoprotein receptor-related protein 6 and apolipoprotein E in AD have been associated with reduced Wnt signaling. In addition, tau phosphorylation is mediated by glycogen synthase kinase-3 (GSK-3), a key antagonist of the Wnt pathway. In this review, we discuss Wnt/beta-catenin signaling in both SAD and FAD, and recapitulate which of its aberrant functions may be critical for (F)AD pathogenesis. We discuss the intriguing possibility that Abeta toxicity may downregulate the Wnt/beta-catenin pathway, thereby upregulating GSK-3 and consequent tau hyperphosphorylation, linking Abeta and tangle pathology. The currently available evidence implies that disruption of tightly regulated Wnt signaling may constitute a key pathological event in AD. In this context, drug targets aimed at rescuing Wnt signaling may prove to be a constructive therapeutic strategy for AD.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其神经病理学特征为β淀粉样蛋白（Aβ）斑块和过度磷酸化的tau蛋白积聚。AD可散发性发生（SAD），或由淀粉样前体蛋白（APP）或早老素-1和-2（PSEN1和PSEN2）基因中的遗传性错义突变引起，导致早发性家族性AD（FAD）。越来越多的证据表明，Wnt/β-连环蛋白依赖性信号通路的改变在两种形式的AD病因中都起作用。早老素参与调节β-连环蛋白的稳定性；因此，与FAD相关的PSEN介导的效应可使Wnt信号通路失调。AD中低密度脂蛋白受体相关蛋白6和载脂蛋白E的基因变异与Wnt信号减弱有关。此外，tau蛋白磷酸化由糖原合酶激酶-3（GSK-3）介导，GSK-3是Wnt信号通路的关键拮抗剂。在本综述中，我们讨论了SAD和FAD中的Wnt/β-连环蛋白信号通路，并概括了其哪些异常功能可能对（F）AD发病机制至关重要。我们讨论了一种有趣的可能性，即Aβ毒性可能下调Wnt/β-连环蛋白通路，从而上调GSK-3并导致tau蛋白过度磷酸化，将Aβ与神经缠结病理联系起来。目前可得的证据表明，紧密调节的Wnt信号通路的破坏可能是AD中的一个关键病理事件。在这种情况下，旨在挽救Wnt信号通路的药物靶点可能被证明是一种有建设性的AD治疗策略。
