Metabolic divergence between healthy and conditional presenilin-1/2 knockout dementia model mice under chronic nicotine exposure

Abstract

Background

Nicotine's complex physiological effects vary significantly between healthy and neurodegenerative states, yet the underlying metabolic mechanisms remain poorly understood.

Objective

To investigate the differential metabolic responses to chronic nicotine administration in healthy versus neurodegenerative conditions and elucidate the underlying biochemical pathways that govern these genotype-dependent effects.

Methods

Eight-month-old presenilin-1/2 double knockout (DKO) mice and wild-type (WT) controls underwent three-month oral nicotine administration (100 μg/mL). We assessed body weight, spontaneous locomotor activity via open field testing, and conducted comprehensive metabolomic analyses using untargeted LC-MS and GC-MS.

Results

Nicotine administration did not significantly affect body weight or locomotor activity in either genotype. In LC-MS, DKO-B mice showed dysregulation in purine metabolism, amino acid pathways, mTOR signaling, and lipolysis compared to WT-B mice. DKO mice showed disruptions in steroid hormone biosynthesis and Fc gamma R-mediated phagocytosis, suggest altered stress responses and immune dysfunction after nicotine administration. In WT mice, distinct changes in amino acid metabolism and drug interaction pathways were observed. In GC-MS, Central carbon metabolism emerged as the most enriched pathway in DKO-B versus WT-B mice. WT-N enrichments included the TCA cycle, cholesterol metabolism, and amino acid pathways, while DKO-N changes involved branched-chain amino acid metabolism, ketone body metabolism, and the pentose phosphate pathway.

Conclusions

Chronic nicotine elicits distinct metabolic responses in healthy versus neurodegenerative conditions. These genotype-specific effects highlight nicotine's potential as a personalized therapeutic agent and metabolic modulator in neurodegenerative disease.