Dergi makalesi Açık Erişim

The Transcriptional Regulatory Properties of Amyloid Beta 1-42 may Include Regulation of Genes Related to Neurodegeneration

2018    Gezen-Ak, Duygu; Atasoy, Irem L.; Candas, Esin; Alaylioglu, Merve; Dursun, Erdinc

Our previous study demonstrated the translocation of A beta 1-42 to the nucleus in response to antibiotic treatment, and interpreted it as a possible transcriptional response of A beta 1-42 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 A beta 1-42 production. For this purpose, we investigated the acute effect of A beta 1-42 on the transcriptional levels of genes that have roles in the mechanisms that produce A beta 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, GSK3 alpha, GSK3 beta, and Cdk5. Additionally, we examined cholecalciferol metabolism-related enzyme 1 alpha-hydroxylase (1 alpha OHase) in primary cortical neurons with qRT-PCR. Our results indicate that A beta 1-42 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 1 alpha OHase genes, and general up-regulation of tau pathway-related genes. We speculate that the presence of A beta impacts the neurons not only with toxic events but also at the transcriptional level. The nuclear localization of A beta 1-42 and its regulatory effects on the target genes that we investigated in present study indicates A beta 1-42 as a transcriptional regulator of genes related to neurodegeneration.