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

Abstract

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.

Ordered and Disordered Segments of Amyloid-β Drive Sequential Steps of the Toxic Pathway

“…One of the predominant hypotheses related to Aβ-mediated toxicity is the disruption of the lipid bilayer membrane . Aβ assemblies cause either generic or specific perturbation, leading to the formation of unregulated ion-channel like structures (“pores”) on the membrane. − Electrostatic interactions between the cell membrane and Aβ oligomers are thought to drive pore formation, which can lead to calcium dis-homeostasis, synapse alteration, and uncontrolled nitric oxide release. ,, Another hypothesis states that major damage is caused by Aβ localized in critical cellular organelles. − There is some evidence that the major location of intracellular Aβ is the endosome-lysosomal system. , There is also some evidence that Aβ binds directly to the DNA and may modulate gene expression. , All these points toward a complex multimodal action of Aβ that needs further detailed investigations in neuronal systems.…”

Looking at Alzheimer’s Disease Pathogenesis from the Nuclear Side

“…Such a sequence is recognized in the promoter of genes involved in AD pathogenesis, including APP , BACE1 , and APOE [ 90 ]. Other works have confirmed that Aβ induces the expression of BACE1 , suggesting a role in the regulation of its own metabolism [ 91 ].…”

“…In concert with these studies, ChIP experiments have shown that Aβ binds the APP promoter [ 92 ], and in SH-SY5Y neuroblastoma cells, Aβ exposure leads to an increase in APP transcription [ 93 ]. Conversely, in cortical primary neurons, Aβ exerts an opposite effect on APP mRNA levels, inducing suppression of its expression [ 91 ]. Moreover, such a discrepancy might be dependent on the dose and the time of exposure and on differences in the regulation mechanisms occurring in diverse kinds of cells.…”

Gene expression profiling of primary fibrochondrocyte cultures in traumatic and degenerative meniscus lesions

“…Ct values obtained from qRT-PCR were used in the formula *DCt ¼ 2 (Geometric mean of reference genes À Ct target gene) to determine relative expression levels of target genes, and Microsoft Office Excel was utilized for calculations and graphics as previously described. 9 Analysis of all comparisons was performed using three different methods:…”