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 Aβ1-42 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 Aβ1-42 oligomers (icvAβ1-42) combined with melatonin deficiency via pinealectomy (pin). We validated this model by assessing spatial memory using the radial arm maze test and measuring Aβ1-42 and γ-secretase levels in the frontal cortex and hippocampus with ELISA. The icvAβ1-42 + pin model experienced impaired spatial memory and increased Aβ1-42 and γ-secretase levels in the frontal cortex and hippocampus, effects not seen with either icvAβ1-42 or the pin alone. Chronic melatonin treatment reversed memory deficits and reduced Aβ1-42 and γ-secretase levels in both structures. Our findings suggest that our icvAβ1-42 + pin model is extremely valuable for future AD research.