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Nicotine attenuates D-galactose- induced hippocampal aging-like alterations with α7-nAChR- associated mechanisms

Year: 2026

Type: article

Abstract: Background Chronic D-galactose exposure produces selected behavioral and cellular changes associated with aging. We examined whether nicotine attenuates these changes and whether its effects differ between wild-type rats and α7 nicotinic acetylcholine receptor (α7-nAChR) knockout rats. Methods Female and male rats received saline, D-galactose (180 mg/kg/day), or D-galactose plus nicotine (0.5 mg/kg/day) for 49 days. We assessed spatial behavior, hippocampal staining and gene expression, and peripheral biochemical measures. Nineteen animal endpoints were analyzed using sex × genotype × treatment models, with multiplicity-adjusted contrasts and unequal-variance sensitivity analyses. Exploratory hippocampal RNA sequencing included six wild-type rats per sex and treatment. Results Compared with wild-type rats receiving D-galactose alone, nicotine-co-treated wild-type rats had shorter latency to first target entry, lower mean distance to the target, and more platform-site crossings in the water maze. They also had higher serum reduced glutathione (GSH) and lower hippocampal astrocytic and microglial immunoreactivity. The nicotine-associated increases in platform-site crossings and serum GSH, and the reduction in hippocampal ionized calcium-binding adapter molecule 1 (IBA1) immunoreactivity, were greater in wild-type than knockout rats. These differences were supported by both variance analyses. Nicotine co-treatment was also associated with reduced senescence-associated β-galactosidase staining and lower hippocampal App , Bace1 , and Psen1 mRNA levels in wild-type rats. Serum amyloid-β1–42 did not change significantly. RNA sequencing identified treatment-associated expression patterns in wild-type hippocampi. Conclusion Nicotine attenuated selected D-galactose-associated behavioral and hippocampal alterations. The genotype comparisons support α7-nAChR-associated modulation of platform-site crossings, serum GSH, and hippocampal IBA1. They do not establish that changes in brain GSH or amyloid production mediate these effects, or that all nicotine responses share one receptor-dependent mechanism.

Source: Frontiers in Aging Neuroscience

DOI: 10.3389/fnagi.2026.1947643