Mitigation of Circadian Disruption-Induced Amyloid Pathology, Neuroinflammation, and Cognitive Disability in C57BL/6J Mice Using Estradiol

Circadian rhythms (CRs) are intrinsic 24 h cycles that regulate critical physiological processes, including sleep-wake behavior, hormonal signaling, and cognition. Disruption of CRs, often caused by chronic aberrant light exposure, has been linked to neurodegenerative diseases such as Alzheimer's disease (AD), through altered expression of core clock genes and neurotransmitter imbalances. Estrogen is a known neuromodulator that influences both circadian timing and cognitive function, yet the mechanistic interplay between estrogen and circadian dysregulation in neurodegeneration remains underexplored. In this study, we investigated whether estradiol could mitigate neuropathological and circadian disturbances induced by chronic, constant light (LL) exposure in female C57BL/6J mice. Mice were exposed to LL for 6 or 10 weeks (LL₆, LL₁₀) to model progressive CR disruption. LL₁₀ significantly delayed locomotor rhythms (<i>p</i> < 0.0001), elevated hippocampal amyloid-β (Aβ) levels (<i>p</i> = 0.0018), and reduced SCN GABA and glutamate levels (<i>p</i> < 0.01), compared to LL₆ and light-dark (LD) controls. Both LL₆ and LL₁₀ also showed decreased hippocampal nitric oxide and glutathione levels (<i>p</i> < 0.05), indicating oxidative stress. Estradiol treatment (1.5 or 3 μg/kg) restored activity rhythms, reduced Aβ accumulation (<i>p</i> = 0.0019), and normalized SCN neurotransmitter levels (GABA; <i>p</i> = 0.0046; glutamate: <i>p</i> = 0.0003). These effects were abrogated by tamoxifen, suggesting estrogen receptor-mediated signaling. Histological analysis further showed that estradiol attenuated hippocampal inflammation and neuronal damage in LL₁₀-exposed animals. These results demonstrate that estrogen protects against circadian disruption-induced neuropathology and supports its potential as a therapeutic agent in mitigating cognitive decline via ER-dependent pathways.