Tapia-Rojas Cheril, Inestrosa Nibaldo C
Centro de Envejecimiento y Regeneración (CARE UC), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
Centro de Envejecimiento y Regeneración (CARE UC), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago; Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia; Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile.
Neural Regen Res. 2018 Oct;13(10):1705-1710. doi: 10.4103/1673-5374.238606.
Alzheimer's disease (AD) is the most common form of dementia in the older population, however, the precise cause of the disease is unknown. The neuropathology is characterized by the presence of aggregates formed by amyloid-β (Aβ) peptide and phosphorylated tau; which is accompanied by progressive impairment of memory. Diverse signaling pathways are linked to AD, and among these the Wnt signaling pathway is becoming increasingly relevant, since it plays essential roles in the adult brain. Initially, Wnt signaling activation was proposed as a neuroprotective mechanism against Aβ toxicity. Later, it was reported that it participates in tau phosphorylation and processes of learning and memory. Interestingly, in the last years we demonstrated that Wnt signaling is fundamental in amyloid precursor protein (APP) processing and that Wnt dysfunction results in Aβ production and aggregation in vitro. Recent in vivo studies reported that loss of canonical Wnt signaling exacerbates amyloid deposition in a transgenic (Tg) mouse model of AD. Finally, we showed that inhibition of Wnt signaling in a Tg mouse previously at the appearance of AD signs, resulted in memory loss, tau phosphorylation and Aβ formation and aggregation; indicating that Wnt dysfunction accelerated the onset of AD. More importantly, Wnt signaling loss promoted cognitive impairment, tau phosphorylation and Aβ production in the hippocampus of wild-type (WT) mice, contributing to the development of an Alzheimer's-like neurophatology. Therefore, in this review we highlight the importance of Wnt/β-catenin signaling dysfunction in the onset of AD and propose that the loss of canonical Wnt signaling is a triggering factor of AD.
阿尔茨海默病（AD）是老年人群中最常见的痴呆形式，然而，该病的确切病因尚不清楚。其神经病理学特征是存在由淀粉样β蛋白（Aβ）肽和磷酸化tau蛋白形成的聚集体；并伴有进行性记忆障碍。多种信号通路与AD相关，其中Wnt信号通路的相关性日益增加，因为它在成人大脑中发挥着重要作用。最初，Wnt信号激活被认为是一种针对Aβ毒性的神经保护机制。后来，有报道称它参与tau蛋白磷酸化以及学习和记忆过程。有趣的是，在过去几年中我们证明Wnt信号在淀粉样前体蛋白（APP）加工中至关重要，并且Wnt功能障碍在体外会导致Aβ的产生和聚集。最近的体内研究报道，在AD转基因（Tg）小鼠模型中，经典Wnt信号的缺失会加剧淀粉样蛋白沉积。最后，我们表明在一只之前已出现AD症状的Tg小鼠中抑制Wnt信号，会导致记忆丧失、tau蛋白磷酸化以及Aβ的形成和聚集；这表明Wnt功能障碍加速了AD的发病。更重要的是，Wnt信号缺失会促进野生型（WT）小鼠海马体中的认知障碍、tau蛋白磷酸化和Aβ产生，从而导致类似阿尔茨海默病的神经病理学发展。因此，在本综述中，我们强调Wnt/β-连环蛋白信号功能障碍在AD发病中的重要性，并提出经典Wnt信号的缺失是AD的一个触发因素。
