Department of Experimental Medicine, University of Genoa, Genoa, Italy.
Department of Pharmacy and Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.
Sci Rep. 2020 Jan 28;10(1):1358. doi: 10.1038/s41598-020-58476-8.
We previously demonstrated that cyclic guanosine monophosphate (cGMP) stimulates amyloid precursor protein (APP) and beta-secretase (BACE1) approximation in neuronal endo-lysosomal compartments, thus boosting the production of amyloid-β (Aβ) peptides and enhancing synaptic plasticity and memory. Here, we further investigated the mechanism by which cGMP regulates the subcellular localization of APP and BACE1, finding that the cyclic nucleotide inhibits the activity of Rab5, a small GTPase associated with the plasma membrane and early endosomes. Accordingly, we also found that expression of a dominant-negative Rab5 mutant increases both APP-BACE1 approximation and Aβ extracellular levels, therefore mimicking the effects induced by cGMP. These results reveal a functional correlation between the cGMP/Aβ pathway and the activity of Rab5 that may contribute to the understanding of Alzheimer's disease pathophysiology.
我们之前的研究表明，环鸟苷酸（cGMP）刺激神经元内溶酶体隔间中淀粉样前体蛋白（APP）和β-分泌酶（BACE1）的接近，从而增加淀粉样β（Aβ）肽的产生，并增强突触可塑性和记忆。在这里，我们进一步研究了 cGMP 调节 APP 和 BACE1 亚细胞定位的机制，发现环核苷酸抑制 Rab5 的活性，Rab5 是一种与质膜和早期内体相关的小 GTPase。因此，我们还发现表达显性失活的 Rab5 突变体增加 APP-BACE1 的接近和 Aβ 的细胞外水平，因此模拟了 cGMP 诱导的作用。这些结果揭示了 cGMP/Aβ 途径与 Rab5 活性之间的功能相关性，这可能有助于理解阿尔茨海默病的病理生理学。
