Transcriptional alteration in TRKβ-SHC isoform as a neuroprotective factor for post stroke memory outcome

BackgroundPost-stroke cognitive impairment (PSCI) affects nearly 30% of stroke survivors and significantly impairs functional recovery. Brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase-{beta} (Trk{beta}) signalling is crucial for synaptic plasticity and cognitive function. While altered expression of truncated TRK{beta}-T1 isoforms has been linked to stroke, the contribution of the TRK{beta}-SHC isoform to PSCI in humans remains poorly understood. ObjectivesThis study aimed to (i) assess isoform-specific expression changes of NTRK2 associated with PSCI, (ii) evaluate the role of an isoform-specific genetic variant in disease susceptibility, and (iii) identify DNA methylation changes regulating NTRK2 expression (if any). MethodsGene expression levels of three major NTRK2 isoforms and MEK2 were analyzed in peripheral blood mononuclear cells from 19 PSCI patients, 21 post-stroke cognitively normal (PSCN) individuals, and 11 healthy controls. Expression data were correlated with raw memory scores and MEK2 expression. DNA methylation profiles of NTRK2 and its transcriptional regulators were assessed using whole-genome bisulfite sequencing. ResultsTRK{beta}-FL expression was significantly reduced in stroke patients compared with controls. In contrast, TRK{beta}-SHC expression was elevated in PSCN individuals relative to PSCI cases and showed a positive correlation with MEK2 expression and memory performance. No significant association was observed between rs65339833 and cognitive subdomains. Gene body hypermethylation, but not promoter methylation, was detected in NTRK2 and its regulatory genes. ConclusionsElevated TRK{beta}-SHC expression may contribute to preserved cognitive function following stroke. DNA methylation status of NTRK2 may regulate alternative splicing and thus represent a novel therapeutic avenue for preventing or mitigating PSCI.