Abstract Number: Esoc2026a2170 Transthyretin as a Biomarker for Post-Stroke Cognitive Impairment: Insights From Dimerization and Thyroid Hormone Signaling

Abstract Background and aims Effective prediction and treatment of post-stroke cognitive impairment (PSCI) remain challenging. Transthyretin (TTR), known clinically as prealbumin, functions as a neuroprotective thyroid hormone carrier. However, its role and structural dynamics in PSCI are still unclear. Methods A PSCI mouse model was established via distal of Middle Cerebral Artery Occlusion with hypoxia. Cognitive function and hippocampal long-term potentiation (LTP) were evaluated. RNA sequencing and Western Blot were used to detect TTR expression and Aβ levels in hippocampal neurons. Conformational changes were visualised by electron microscope. TTR tetramers were injected in PSCI mice to measured changes. Clinically, serum prealbumin (TTR) and Aβ levels were measured in 22 PSCI patients and 19 age-matched healthy controls in a case-control design. Results PSCI mice exhibited spatial memory deficits and impaired LTP. Furthermore, they showed increased TTR expression and Aβ level. Clinically, PSCI patients also exhibited significantly elevated serum prealbumin tetramers and Aβ levels versus controls, despite comparable baseline characteristics. Although hippocampal neurons showed a compensatory upregulation of TTR transcription, the synthesized TTR existed exclusively in its dimeric form. Injecting TTR tetramers upregulated thyroid hormone signaling pathway and improve spatial memory in PSCI mice. Conclusions TTR dimerization and thyroid hormone signaling dysregulation contribute to PSCI pathogenesis. Elevated serum TTR tetramers may reflect a compensatory response to clear Aβ. TTR shows promise as a biomarker, and targeting its structure or downstream pathways may offer a novel therapeutic strategy for PSCI. Conflict of interest Zhiyu Leng, Xiaoyi Jiang, Ming Yuan, Qinxue Sun, Yuhualei Pan, Gang Li:nothing to disclose