Brain and Neurodegenerative Disorders Research Laboratory, Department of Medical Biology, Cerrahpasa Faculty of Medicine, Istanbul University, 34098, Istanbul, Turkey.
Neuromolecular Med. 2018 Sep;20(3):363-375. doi: 10.1007/s12017-018-8498-6. Epub 2018 Jun 12.
Our previous study demonstrated the translocation of Aβ1-42 to the nucleus in response to antibiotic treatment, and interpreted it as a possible transcriptional response of Aβ1-42 to antibiotics. The present study aims to investigate how amyloid acts on the key elements of neurodegeneration and the molecules involved in the induction of Aβ1-42 production. For this purpose, we investigated the acute effect of Aβ1-42 on the transcriptional levels of genes that have roles in the mechanisms that produce Aβ itself: alpha secretase (ADAM10), beta secretase (BACE1), the gamma secretase complex (PS-1, PS-2, Nicastrin), the substrate APP, APOE (the significant risk factor for sporadic form of the AD), TREM2 (recently indicated as a contributor to AD risk), NMDAR subunits and PKCzeta (contributors of memory and learning), and key elements of tau pathology such as tau, GSK3α, GSK3β, and Cdk5. Additionally, we examined cholecalciferol metabolism-related enzyme 1α-hydroxylase (1αOHase) in primary cortical neurons with qRT-PCR. Our results indicate that Aβ1-42 has an effect on most of the target genes. This effect involves regulation of the amyloidogenic pathway in a complex manner, specifically, a general downregulation in NMDARs, ApoE, Trem2, and 1αOHase genes, and general up-regulation of tau pathway-related genes. We speculate that the presence of Aβ impacts the neurons not only with toxic events but also at the transcriptional level. The nuclear localization of Aβ1-42 and its regulatory effects on the target genes that we investigated in present study indicates Aβ1-42 as a transcriptional regulator of genes related to neurodegeneration.
我们之前的研究表明，抗生素治疗会导致 Aβ1-42 向细胞核易位，并将其解释为 Aβ1-42 对抗生素的可能转录反应。本研究旨在探讨淀粉样蛋白如何作用于神经退行性变的关键因素和诱导 Aβ1-42 产生的相关分子。为此，我们研究了 Aβ1-42 对参与 Aβ 自身产生机制的基因转录水平的急性影响：α 分泌酶（ADAM10）、β 分泌酶（BACE1）、γ 分泌酶复合物（PS-1、PS-2、Nicastrin）、底物 APP、APOE（散发性 AD 的重要危险因素）、TREM2（最近被认为是 AD 风险的贡献者）、NMDAR 亚基和 PKCzeta（记忆和学习的贡献者），以及 tau 病理学的关键因素，如 tau、GSK3α、GSK3β 和 Cdk5。此外，我们还通过 qRT-PCR 检查了原代皮质神经元中的胆钙化醇代谢相关酶 1α-羟化酶（1αOHase）。我们的结果表明，Aβ1-42 对大多数靶基因都有影响。这种影响涉及到淀粉样蛋白途径的复杂调节，具体来说，NMDARs、ApoE、Trem2 和 1αOHase 基因普遍下调，tau 途径相关基因普遍上调。我们推测，Aβ 的存在不仅会对神经元产生毒性作用，还会在转录水平上产生影响。Aβ1-42 的核定位及其对我们在本研究中研究的靶基因的调节作用表明，Aβ1-42 是与神经退行性变相关基因的转录调节剂。
