Melatonin Supplementation Alleviates Impaired Spatial Memory by Influencing AβMetabolism via γ-Secretase in the icvAβRat Model with Pinealectomy.

Abstract

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 Aβpeptides, 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 Aβoligomers (icvAβ) combined with melatonin deficiency via pinealectomy (pin). We validated this model by assessing spatial memory using the radial arm maze test and measuring Aβand γ-secretase levels in the frontal cortex and hippocampus with ELISA. The icvAβ+ pin model experienced impaired spatial memory and increased Aβand γ-secretase levels in the frontal cortex and hippocampus, effects not seen with either icvAβor the pin alone. Chronic melatonin treatment reversed memory deficits and reduced Aβand γ-secretase levels in both structures. Our findings suggest that our icvAβ+ pin model is extremely valuable for future AD research.