Melatonin Supplementation Alleviates Impaired Spatial Memory by Influencing Aβ Metabolism via γ-Secretase in the icvAβ Rat Model with Pinealectomy.

In the search for Alzheimer's disease (AD) therapies, most animal models focus on familial AD, which accounts for a small fraction of cases. The majority of AD cases arise from stress factors, such as oxidative stress, leading to neurological changes (sporadic AD). Early in AD progression, dysfunction in γ-secretase causes the formation of insoluble Aβ peptides, which aggregate into senile plaques, triggering neurodegeneration, cognitive decline, and circadian rhythm disturbances. To better model sporadic AD, we used a new AD rat model induced by intracerebroventricular administration of Aβ oligomers (icvAβ) combined with melatonin deficiency via pinealectomy (pin). We validated this model by assessing spatial memory using the radial arm maze test and measuring Aβ and γ-secretase levels in the frontal cortex and hippocampus with ELISA. The icvAβ + pin model experienced impaired spatial memory and increased Aβ and γ-secretase levels in the frontal cortex and hippocampus, effects not seen with either icvAβ or the pin alone. Chronic melatonin treatment reversed memory deficits and reduced Aβ and γ-secretase levels in both structures. Our findings suggest that our icvAβ + pin model is extremely valuable for future AD research.