Endocannabinnoids innervate Circadian mechinary mitigating neuroinflammation, amyloidogenesis and cognition phenotypic to AD

Aim: Circadian rhythm disruption (CRd) caused by inappropriate light exposure is associated with cognitive impairment and Alzheimer’s disease (AD)-like changes. Since endocannabinoid signaling regulates circadian resetting and exhibits neuroprotective properties, this study evaluated whether cannabinoid modulation could attenuate light-induced CRd and associated AD-like alterations. Methods: Mice were maintained under 12:12 h light-dark (LD), constant darkness (DD), or constant light (LL) conditions. Cannabinoid receptor agonists CP-55,940 (0.1 and 0.5 mg/kg) and WIN 55,212-2 (1 and 2 mg/kg) were administered. Circadian activity, cognitive performance, and associated molecular and biochemical alterations were assessed. Results: Constant LL exposure induced complete arrhythmicity and impaired recognition, working, and spatial reference memory. Retinal Cnr1 expression was altered, while glutamate and GABA levels and c-Fos, Per2, Cnr1, and Gabrg2 expression were dysregulated in the suprachiasmatic nucleus. In the hippocampus and cortex, reduced glutathione and Sirt1, increased nitric oxide and altered Cnr2, elevated Bace1 and soluble Aβ1-42, and altered Gabrg2, Gabbr1, and Cnr1 indicated oxidative stress, neuroinflammatory changes, amyloidogenesis, and altered excitation-inhibition signaling. Both agonists restored activity rhythmicity, improved learning and memory, and attenuated these alterations. Conclusion: Cannabinoid receptor activation attenuated chronic constant light-induced CRd, cognitive impairment, and associated AD-like molecular changes, suggesting its potential in managing CRd-associated cognitive decline.