Transcriptome Profile of Nicotinic Receptor-Linked Sensitization of Beta Amyloid Neurotoxicity.

ABSTRACT: Understanding the specific gene changes underlying the prodromic stages of Alzheimer's disease pathogenesis will aid the development of new, targeted therapeutic strategies for this neurodegenerative disorder. Here, we employed RNA-sequencing to analyze global differential gene expression in a defined model nerve cell line expressing ?4?2 nicotinic receptors (nAChRs), high-affinity targets for beta amyloid (A?). The nAChR-expressing neuronal cells were treated with nanomolar A?1-42 to gain insights into the molecular mechanisms underlying A?-induced neurotoxicity in the presence of this sensitizing target receptor. We identified 15 genes (out of 15,336) that were differentially expressed upon receptor-linked A? treatment. Genes up-regulated with A? treatment were associated with calcium signaling and axonal vesicle transport (including the ?4 nAChR subunit, the calcineurin regulator RCAN3, and KIF1C of the kinesin family). Downregulated genes were associated with metabolic, apoptotic or DNA repair pathways (including APBA3, PARP1 and RAB11). Validation of the differential expression was performed via qRT-PCR and immunoblot analysis in the defined model nerve cell line and primary mouse neurons. Further verification was performed using immunocytochemistry. In conclusion, we identified apparent changes in gene expression on A? treatment in the presence of the sensitizing nAChRs, linked to early-stage A?-induced neurotoxicity, which may represent novel therapeutic targets.

SUBMITTER: Arora K 

PROVIDER: S-EPMC7105468 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature