Chronic Smoking Impairs Glymphatic Transport and Cognitive Function in Adolescent Mice Through Cardiac, Vascular, and Perivascular Aquaporin-4 Mechanisms.

AIMS: Smoking significantly impairs cognitive function and is a major risk factor for dementia, particularly when initiated during adolescence, a critical period for brain development. The glymphatic system, which is thought to participate in metabolic waste clearance, has been implicated in maintaining cognitive health. This study investigates the effects of chronic smoking on glymphatic transport and its underlying mechanisms.

METHODS

Glymphatic transport was assessed using immunofluorescence and two-photon microscopy, while phosphorylated tau accumulation in the dentate gyrus (DG) was examined via immunohistochemical staining. Synaptogenesis and neurogenesis in the hippocampal DG were analyzed using synaptophysin, PSD-95, doublecortin, and standard histological techniques. Cognitive function was measured through the Morris water maze (MWM) test and novel object recognition (NOR) tests, with cardiac function assessed by echocardiography.

RESULTS

The findings indicate that chronic smoking leads to a duration-dependent disruption of glymphatic transport, resulting in the accumulation of phosphorylated tau in the hippocampal DG, reduced synaptogenesis and neurogenesis, and subsequent cognitive decline.

CONCLUSION

This glymphatic dysfunction may be associated with impaired cardiac ejection, diminished arterial pulsatility, and loss of perivascular aquaporin-4 (AQP4), collectively contributing to smoking-related cognitive impairment.