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bioRxiv · 10.1101/2024.09.14.613003

DIFFERENTIAL REGULATION OF GENES IN ENTORHINAL CORTEX AND HIPPOCAMPUS IN LATE ONSET AD

Biswas, M.·Basu, S.
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Abstract

Amyloidogenic processing of APP mediated by increased BACE1 activity resulting in A{beta} production and accumulation of hyperphosphorylated tau cause neuronal degeneration in AD. Pathological changes occur early in the EC and the hippocampus, much before neurodegeneration sets in. Here, using 500 and 303 differentially expressed genes from the EC and hippocampus respectively, we observed impairment of several cellular functions owing to either disrupted transcription or post-translational regulation, through functional enrichment, PPI network, miRNA and convergent functional genomic analysis. In EC, functional enrichment analysis highlighted several processes of which the Oncostatin-M-mediated pathway is related in the disease pathogenesis by increasing BACE1 transcription through STAT3 activation. Hub genes, BRD4 and PIN1, involved in A{beta} and tau pathology are downregulated probably through the concerted action of hsa-miR-3613-3p and hsa-miR-4674, upregulated miRNAs in AD. In the hippocampus, upregulated FXR1 and downregulated RTN3 being involved in post-transcriptional processing of BACE1, result in increased A{beta} production. For the disruption observed in the autophagy-lysosomal pathway, neurotransmitter synthesis and A{beta} clearance, YWHAH, a downregulated hub gene is instrumental. Regulation of YWHAH expression is probably mediated at the post-transcriptional level through hsa-miR-455-3p and hsa-miR-4674, known to be heavily upregulated in AD. In both the regions, similar pattern of disrupted cellular pathways emerge, although the key players, differ. Whereas dysfunctional proteasomal degradation is mediated by SKP1-CUL1 in EC, it is CUL3 mediated in hippocampus. Thus, similar disease pathology develops through dysregulation of pathways that are evidently different in EC and hippocampus implying failure of therapeutics based on single target.

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Biswas, M., Basu, S.. 2024-09-19. DIFFERENTIAL REGULATION OF GENES IN ENTORHINAL CORTEX AND HIPPOCAMPUS IN LATE ONSET AD. https://doi.org/10.1101/2024.09.14.613003

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