Menet Romain, Bourassa Philippe, Calon Frédéric, ElAli Ayman
Neuroscience Axis, Research Center of CHU de Québec - Université Laval, Quebec City, QC, Canada; Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Quebec City, QC, Canada.
Neuroscience Axis, Research Center of CHU de Québec - Université Laval, Quebec City, QC, Canada; Faculty of Pharmacy, Université Laval, Quebec City, QC, Canada.
Neurochem Int. 2020 Dec;141:104881. doi: 10.1016/j.neuint.2020.104881. Epub 2020 Oct 15.
Alzheimer's disease (AD) constitutes the leading cause of dementia worldwide. It is associated to amyloid-β (Aβ) aggregation and tau hyper-phosphorylation, accompanied by a progressive cognitive decline. Evidence suggests that the canonical Wnt pathway is deregulated in AD. Pathway activity is mediated by β-catenin stabilization in the cytosol, and subsequent translocation to the nucleus to regulate the expression of several genes implicated in brain homeostasis and functioning. It was recently proposed that Dickkopf-related protein-1 (DKK1), an endogenous antagonist of the pathway, might be implicated in AD pathogenesis. Here, we hypothesized that canonical Wnt pathway deactivation associated to DKK1 induction contributes to late-onset AD pathogenesis, and thus DKK1 neutralization could attenuate AD pathology. For this purpose, human post-mortem AD brain samples were used to assess pathway activity, and aged APPswe/PS1 mice were used to investigate DKK1 in late-onset AD-like pathology and therapy. Our findings indicate that β-catenin levels progressively decrease in the brain of AD patients, correlating with the duration of symptoms. Next, we found that Aβ pathology in APPswe/PS1 mediates DKK1 induction in the brain. Pharmacological neutralization of DKK1's biological activity in APPswe/PS1 mice restores pathway activity by stabilizing β-catenin, attenuates Aβ pathology, and ameliorates the memory of mice. Attenuation of AD-like pathology upon DKK1 inhibition is accompanied by a reduced protein expression of beta-site amyloid precursor protein (APP) cleaving enzyme-1 (BACE1). Moreover, DKK1 inhibition enhances vascular density, promotes blood-brain barrier (BBB) integrity by increasing claudin 5, glucose transporter-1 (GLUT1), and ATP-binding cassette sub-family B member-1 (ABCB1) protein expression, as well as ameliorates synaptic plasticity by increasing brain-derived neurotrophic factor (BDNF), and postsynaptic density protein-95 (PSD-95) protein expression. DKK1 conditional induction reduces claudin 5, abcb1, and psd-95 mRNA expression, validating its inhibition effects. Our results indicate that neutralization of DKK1's biological activity attenuates AD-like pathology by restoring canonical Wnt pathway activity.
阿尔茨海默病（AD）是全球痴呆症的主要病因。它与淀粉样β蛋白（Aβ）聚集和tau蛋白过度磷酸化有关，伴有进行性认知衰退。有证据表明，经典Wnt信号通路在AD中失调。该信号通路的活性由细胞质中β-连环蛋白的稳定介导，随后转运至细胞核以调节与脑内稳态和功能相关的多个基因的表达。最近有人提出，该信号通路的内源性拮抗剂Dickkopf相关蛋白1（DKK1）可能与AD发病机制有关。在此，我们假设与DKK1诱导相关的经典Wnt信号通路失活促成了晚发性AD的发病机制，因此DKK1的中和作用可能减轻AD病理。为此，我们使用人类AD尸检脑样本评估信号通路活性，并使用老年APPswe/PS1小鼠研究DKK1在晚发性AD样病理和治疗中的作用。我们的研究结果表明，AD患者大脑中β-连环蛋白水平逐渐降低，与症状持续时间相关。接下来，我们发现APPswe/PS1中的Aβ病理介导了大脑中DKK1的诱导。在APPswe/PS1小鼠中对DKK1的生物学活性进行药理中和，可通过稳定β-连环蛋白恢复信号通路活性，减轻Aβ病理，并改善小鼠的记忆。抑制DKK1后AD样病理的减轻伴随着β-位点淀粉样前体蛋白（APP）裂解酶-1（BACE1）蛋白表达的降低。此外，抑制DKK1可增加血管密度，通过增加闭合蛋白5、葡萄糖转运蛋白-1（GLUT1）和ATP结合盒亚家族B成员-1（ABCB1）蛋白表达促进血脑屏障（BBB）完整性，以及通过增加脑源性神经营养因子（BDNF）和突触后密度蛋白-95（PSD-95）蛋白表达改善突触可塑性。DKK1条件性诱导降低了闭合蛋白5、abcb1和psd-9 mRNA表达，证实了其抑制作用。我们的结果表明，中和DKK1的生物学活性可通过恢复经典Wnt信号通路活性减轻AD样病理。
