Cardiovascular

Transcriptional Alteration in TRKβ-SHC Isoform as a Neuroprotective Factor for Post-Stroke Memory Outcomes.

Sadhukhan D, Chowdhury R, et al. • The European journal of neuroscience • 2026

TL;DR

TRKβ-SHC expression may be associated with preserved cognitive function after stroke, with findings indicating a potential relationship between isoform-specific NTRK2 expression, genetic regulation, and cognitive outcomes in post-stroke cognitive impairment.

Key Findings

Results

TRKβ-FL mRNA expression was significantly reduced in stroke patients compared with healthy controls.

Isoform-specific expression was analysed in 50 subjects (stroke patients vs. healthy controls)
Blood was used as the primary biosource for expression analysis
TRKβ-FL refers to the full-length isoform of the NTRK2/TRKβ receptor
The reduction was observed regardless of post-stroke cognitive status

Results

TRKβ-SHC expression was higher in post-stroke cognitively normal (PSCN) individuals than in post-stroke cognitive impairment (PSCI) patients.

Isoform-specific expression was analysed in 50 subjects
TRKβ-SHC is a truncated isoform of the NTRK2 gene containing the SHC-binding domain
Higher TRKβ-SHC expression was found in cognitively preserved stroke survivors compared to those with cognitive impairment
This finding suggests TRKβ-SHC may serve as a neuroprotective factor for post-stroke cognitive outcomes

Results

TRKβ-SHC expression showed a positive correlation with both MEK2 expression and memory performance.

The correlation was assessed using blood-based mRNA expression data
MEK2 is a downstream signaling component in the BDNF-TRKβ pathway relevant to synaptic plasticity
Memory performance was assessed as part of cognitive outcome evaluation in stroke patients
This correlation suggests a functional downstream signaling link between TRKβ-SHC and cognitive preservation

Results

The 'TT' genotype of the rs6559833 variant showed marginal associations with post-stroke memory status and overall BMSE scores.

rs6559833 was genotyped in 280 ischemic stroke patients
Association with post-stroke memory status: p = 0.0442
Association with overall BMSE (Bengali Mental Status Examination) scores: p = 0.0488
rs6559833 is described as an isoform-specific variant of NTRK2
The associations were described as 'marginal'

Results

Hypermethylation was observed within the NTRK2 gene body and in genes encoding its splicing regulators, with no evident difference in promoter methylation.

DNA methylation was assessed in 10 samples using whole-genome bisulfite sequencing (WGBS)
Blood was used as the primary biosource for methylation analysis
Hypermethylation was found specifically in the gene body region of NTRK2, not in the promoter region
Genes encoding splicing regulators of NTRK2 also showed hypermethylation, suggesting epigenetic regulation of isoform expression
The absence of promoter methylation differences suggests isoform-specific regulation may be driven by gene body methylation affecting splicing rather than overall transcription

Background

Post-stroke cognitive impairment (PSCI) affects nearly 30% of stroke survivors and substantially limits functional recovery.

This figure is cited as epidemiological context for the study
PSCI was the primary cognitive outcome studied in 280 ischemic stroke patients
BDNF-TRKβ signalling is stated to play an important role in synaptic plasticity and cognitive function
The contribution of individual NTRK2/TRKβ isoforms to PSCI was described as 'poorly understood' prior to this study

What This Means

This research suggests that a specific variant of a brain growth factor receptor protein — called TRKβ-SHC — may help protect memory after a stroke. The researchers studied blood samples from stroke patients and healthy individuals, examining how different versions (isoforms) of the NTRK2 gene are expressed, how a specific genetic variant relates to cognitive outcomes, and whether DNA chemical modifications (methylation) might regulate which version of the gene is active. They found that while the full-length version of the receptor (TRKβ-FL) was reduced in all stroke patients, the truncated version (TRKβ-SHC) was notably higher in stroke survivors who maintained normal cognition compared to those who developed memory problems. This TRKβ-SHC expression also correlated with activity in a related signaling molecule (MEK2) and with better memory test scores. The study also found that a specific genetic spelling variant (rs6559833, with the 'TT' version) showed a borderline statistical association with better memory outcomes after stroke. Additionally, chemical tags (methylation marks) were found on the body of the NTRK2 gene and on genes that control how the gene is spliced into different versions, though not on the gene's on/off switch (promoter). This pattern suggests the body's epigenetic machinery may influence which isoform of TRKβ gets produced after stroke. This research matters because it points toward TRKβ-SHC as a potential biomarker or therapeutic target for post-stroke cognitive impairment, which affects roughly 30% of stroke survivors. The findings are preliminary — based on relatively small sample sizes for some analyses — but they open a direction for understanding why some stroke survivors maintain memory function while others do not, potentially through isoform-specific regulation of a key brain plasticity pathway.

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Citation

Sadhukhan D, Chowdhury R, Roy S, Roy A, Maitra S, Ghosh K, et al.. (2026). Transcriptional Alteration in TRK&#x3b2;-SHC Isoform as a Neuroprotective Factor for Post-Stroke Memory Outcomes.. The European journal of neuroscience. https://doi.org/10.1111/ejn.70684

Key Findings

What This Means

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