Cisternas Pedro, Oliva Carolina A, Torres Viviana I, Barrera Daniela P, Inestrosa Nibaldo C
Centro de Envejecimiento y Regeneración, Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
Front Cell Neurosci. 2019 Jul 18;13:295. doi: 10.3389/fncel.2019.00295. eCollection 2019.
Alzheimer's disease (AD) is the most common type of dementia. The onset and progression of this pathology are correlated with several changes in the brain, including the formation of extracellular aggregates of amyloid-beta (Aβ) peptide and the intracellular accumulation of hyperphosphorylated tau protein. In addition, dysregulated neuronal plasticity, synapse loss, and a reduction in cellular energy metabolism have also been described. Canonical Wnt signaling has also been shown to be downregulated in AD. Remarkably, we showed previously that the inhibition of Wnt signaling accelerates the appearance of AD markers in transgenic (Tg) and wild-type (WT) mice. Additionally, we found that Wnt signaling stimulates energy metabolism, which is critical for the ability of Wnt to promote the recovery of cognitive function in AD. Therefore, we hypothesized that activation of canonical Wnt signaling in a presymptomatic transgenic animal model of AD would improve some symptoms. To explore the latter, we used a transgenic mouse model (J20 Tg) with mild AD phenotype expression (high levels of amyloid aggregates) and studied the effect of (ANDRO), an activator of canonical Wnt signaling. We found that presymptomatic administration of ANDRO in J20 Tg mice prevented the reduction in cellular energy metabolism markers. Moreover, treated animals showed improvement in cognitive performance. At the synaptic level, J20 Tg animals showed severe deficiencies in presynaptic function as determined by electrophysiological parameters, all of which were completely restored to normal by ANDRO administration. Finally, an analysis of hippocampal synaptosomes by electron microscopy revealed that the length of synapses was restored with ANDRO treatment. Altogether, these data support the idea that the activation of canonical Wnt signaling during presymptomatic stages could represent an interesting pharmacological strategy to delay the onset of AD.
阿尔茨海默病（AD）是最常见的痴呆类型。这种病理状态的发生和进展与大脑中的多种变化相关，包括淀粉样β（Aβ）肽细胞外聚集体的形成以及过度磷酸化tau蛋白的细胞内积累。此外，还描述了神经元可塑性失调、突触丧失和细胞能量代谢降低。经典Wnt信号通路在AD中也被证明下调。值得注意的是，我们之前表明抑制Wnt信号通路会加速转基因（Tg）和野生型（WT）小鼠中AD标志物的出现。此外，我们发现Wnt信号通路刺激能量代谢，这对于Wnt促进AD认知功能恢复的能力至关重要。因此，我们假设在AD症状前转基因动物模型中激活经典Wnt信号通路会改善一些症状。为了探究后者，我们使用了具有轻度AD表型表达（高水平淀粉样聚集体）的转基因小鼠模型（J20 Tg），并研究了经典Wnt信号通路激活剂（ANDRO）的作用。我们发现，在J20 Tg小鼠症状前给予ANDRO可防止细胞能量代谢标志物的减少。此外，接受治疗的动物在认知表现上有所改善。在突触水平，通过电生理参数测定，J20 Tg动物在突触前功能方面表现出严重缺陷，而给予ANDRO后所有这些缺陷都完全恢复正常。最后，通过电子显微镜对海马突触体进行分析发现，ANDRO治疗可使突触长度恢复。总之，这些数据支持这样一种观点，即在症状前阶段激活经典Wnt信号通路可能是一种有趣的药理学策略，可延缓AD的发病。
