TERT activator compound alleviates cigarette smoke-induced cognitive deficits by modulating hippocampal inflammation and neurogenesis: A comprehensive study integrating Mendelian randomization

Cigarette smoking represents a major public health concern, yet its relationship with cognitive function remains controversial. Here, we integrated two-sample Mendelian randomization (MR) with an in vivo model to interrogate this relationship and evaluate a telomerase-based intervention. Two-sample MR provided genetic evidence for a causal effect of smoking behaviors on increased Alzheimer's disease (AD) risk in East Asian and European populations. Guided by these findings, we established a mouse model of cigarette smoke exposure using cigarette smoke extract (CSE) and confirmed significant neurocognitive impairment by fear conditioning and Y-maze behavioral tests. We also found that CSE elicited robust hippocampal inflammation, evidenced by increased IBA1 and elevated pro-inflammatory cytokines (IL-6, IL-1β, TNF-α). This inflammatory milieu was accompanied by reduced hippocampal brain-derived neurotrophic factor (BDNF) and compromised adult hippocampal neurogenesis (AHN), reflected by decreased doublecortin (DCX) expression. Bulk RNA sequencing with gene set enrichment analysis indicated downregulation of telomere maintenance gene set after CSE exposure, and RT-qPCR and Western blotting verified the suppression of telomerase reverse transcriptase (TERT) in the hippocampus. Notably, intraperitoneal administration of a TERT activator compound (TAC) to CSE-treated mice restored hippocampal TERT expression, attenuated neuroinflammation, enhanced BDNF levels and AHN, and ameliorated cognitive deficits. To sum up, our findings integrate population-based genetic evidence with experimental validation to show that cigarette smoke exposure impairs cognition and that pharmacologic activation of TERT confers neuroprotection, highlighting TERT as a promising therapeutic target for smoking-related cognitive disorders.