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Abstract：
Wnt and R-spondin (Rspo) proteins are two major types of endogenous Wnt/β-catenin signaling agonists. While Wnt/β-catenin signaling is greatly diminished in Alzheimer\'s disease (AD), it remains to be elucidated whether the inhibition of this pathway is associated with dysregulation of Wnt and Rspo proteins. By analyzing temporal cortex RNA-seq data of the human postmortem brain samples, we found that WNT1 and RRPO2 were significantly downregulated in human AD brains. In addition, the expression of Wnt acyltransferase porcupine (PORCN), which is essential for Wnt maturation and secretion, was greatly deceased in these human AD brains. Interestingly, the lowest levels of WNT1, PORCN, and RSPO2 expression were found in human AD brains carrying two copies of APOE4 allele, the strongest genetic risk factor of late-onset AD. Importantly, there were positive correlations among the levels of WNT1, PORCN, and RSPO2 expression in human AD brains. Supporting observations in humans, Wnt1, PORCN, and Rspo2 were downregulated and Wnt/β-catenin signaling was diminished in the 5xFAD amyloid model mice. In human APOE-targeted replacement mice, downregulation of WNT1, PORCN, and RSPO2 expression was positively associated with aging and APOE4 genotype. Finally, WNT1 and PORCN expression and Wnt/β-catenin signaling were inhibited in human APOE4 iPSC-derived astrocytes when compared to the isogenic APOE3 iPSC-derived astrocytes. Altogether, our findings suggest that the dysregulations of Wnt1, PORCN, and Rspo2 could be coordinated together to diminish Wnt/β-catenin signaling in aging- and APOE4-dependent manners in the AD brain.
摘要：
Wnt和R-spondin(Rspo)蛋白是两种主要类型的内源性Wnt/β-连环蛋白信号传导激动剂。虽然Wnt/β-catenin信号在阿尔茨海默病（AD）中大大减少，该途径的抑制是否与Wnt和Rspo蛋白的失调有关还有待阐明。通过分析人类死后大脑样本的颞叶皮层RNA-seq数据，我们发现WNT1和RRPO2在人类AD脑中显著下调。此外,豪猪Wnt酰基转移酶（PORCN）的表达，这对Wnt成熟和分泌至关重要，在这些人类AD大脑中大大死亡。有趣的是,WNT1，PORCN的最低水平，在携带两个APOE4等位基因拷贝的人类AD大脑中发现RSPO2表达，晚发性AD的最强遗传危险因素。重要的是,WNT1、PORCN、和RSPO2在人类AD大脑中的表达。支持人类的观察，Wnt1,PORCN,在5xFAD淀粉样蛋白模型小鼠中，Rspo2下调，Wnt/β-catenin信号传导减弱。在人类APOE靶向替代小鼠中，下调WNT1、PORCN、RSPO2表达与衰老和APOE4基因型呈正相关。最后,与等基因APOE3iPSC衍生的星形胶质细胞相比，人APOE4iPSC衍生的星形胶质细胞中的WNT1和PORCN表达和Wnt/β-catenin信号传导受到抑制。总之,我们的研究结果表明，Wnt1、PORCN、和Rspo2可以协调在一起以在AD脑中以年龄和APOE4依赖性方式减少Wnt/β-catenin信号传导。
