Alzheimer’s disease is the most common form of dementia characterized by a progressive deterioration of cognitive functions and by overproduction of toxic form of β-amyloid (Aβ) and intracellular accumulation of the microtubule-associated protein tau into neurofibrillary tangles (NFTs). In the past few years, our research team has investigated the genetic variability of PSEN1, PSEN2 and APP genes in AD patients, especially familial early-onset AD (fEOAD). We have identified mutations in PSEN1 and PSEN2, including novel ones located in exons coding for the large cytosolic loop of presenilin 1. To test functional nature of the aforementioned mutations we have performed analysis of the whole transcriptome using RNA sequencing method and total RNA isolated from primary fibroblasts cultures derived from fEOAD patients. Using RNA-Seq data we have performed differential gene expression (DGE) analysis, which was estimated by three independent bioinformatic tools (i.e. Cuffdiff, EgdeR and Deseq2). Further DGE enrichment analysis revealed a number of signaling pathways significantly altered in the samples from fEOAD patients, which varied depending on identified mutations in PSEN1 or PSEN2 genes. Next to cell cycle, pro-apoptotic, TNF, adherent junction, p53, or Wnt signaling pathways, we have found several changes in the pathways that have not been previously linked to AD. Among the aforementioned pathways we have focused on HIF-1 signaling, Hippo signaling as well as DNA mismatch repair, base excision repair, and transcriptional misregulation mechanisms. Interestingly, two novel PSEN1 mutations changing the amino acid sequence of the large cytoplasmic loop have been linked to TNF and HIF-1 signaling pathways, suggesting induction of proinflammatory response and opening future directions of the research on fEOAD pathomechanism. Supported by NCN G1119-2013/09/D/NZ3/01348.
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