Targeting Neuroinflammation in Alzheimer’s Disease with a Nicotinic Metabolite: Insights from the 5xFAD Mouse Model

Introduction: Alzheimer’s disease (AD) is characterized by progressive cognitive decline and is largely driven by amyloid-β aggregation, tau hyperphosphorylation and widespread synaptic dysfunction. Chronic neuroinflammation, associated with altered cytokine signalling, plays a significant role in the progression of AD. Although nicotine has been shown to influence inflammatory pathways, its therapeutic use is constrained by adverse effects. 6-hydroxy-L-nicotine (6HLN), a nicotine metabolite, may exhibit anti-inflammatory activity while offering a more favorable safety profile. In this context, the present study examines the effects of 6HLN on specific molecular markers of inflammatory cytokine signalling to assess its potential biological relevance in AD-associated pathology.

Methods: The effects of chronic 6HLN treatment were evaluated in a 5xFAD transgenic mouse model of AD. 5xFAD mice underwent chronic intraperitoneal administration of 6HLN at two doses (0.3 and 0.6mg/kg for 30 days). Key inflammatory mediators (NF-κB, IL-6 and TNF-α) were quantified from brain homogenates using ELISA.

Results: 6HLN induced a dose-dependent reduction in NF-κB, IL-6 and TNF-α levels, indicating a significant attenuation of pro-inflammatory cytokine response in 5xFAD mice.

Conclusion: These findings suggest that 6HLN may serve as a promising anti-inflammatory candidate for mitigating inflammation-related pathological processes in AD. This work was supported by CNCSIS-UEFISCSU, project number PN-III-P4-PCE-2021-1692.