Age- and Genotype-Dependent Effects of Chronic Nicotine on Presenilin1/2 Double Knockout Mice: From Behavior to...

The potential therapeutic role of nicotine in Alzheimer's disease (AD) remains controversial, particularly regarding its age-dependent effects and underlying mechanisms.

This study investigated the impact of chronic nicotine administration on cognitive function and molecular pathways in Presenilin 1/2 double knockout (DKO) mice, an amyloid-β: (Aβ:)- independent model of AD. Three-month-old and eight-month-old DKO and wild-type (WT) mice received oral nicotine treatment (100 μg/ml) for three months. Behavioral assessments revealed that while the 6-month-old cohort showed no significant differences between nicotine-treated and control groups regardless of genotype, nicotine improved contextual fear memory in 11-month- old DKO mice but impaired nest-building ability and cued fear memory in age-matched WT controls. Transcriptome analysis of the prefrontal cortex identified distinct molecular responses to nicotine between genotypes.

In DKO mice, nicotine modulated neuropeptide signaling and reduced astrocyte activation, while in WT mice, it disrupted cytokine-cytokine receptor interaction and neuroactive ligand- receptor interaction pathways. Western blot analysis revealed that nicotine treatment significantly reduced tau hyperphosphorylation and Glial Fibrillary Acidic Protein (GFAP) expression in 11-month-old DKO mice, which was further confirmed by immunohistochemistry showing decreased astrocyte activation in multiple brain regions

These findings demonstrate that nicotine's effects on cognition and molecular pathways are both age- and genotype-dependent, suggesting its therapeutic potential may be limited to specific stages of neurodegeneration while potentially having adverse effects in healthy aging brains.