Novel Multitarget Directed Tacrine Hybrids as Anti-Alzheimer's Compounds Improved Synaptic Plasticity and Cognitive Impairment in APP/PS1 Transgenic Mice

Alzheimer's disease (AD) is a complex pathological neurodegenerative disease that seriously threatens human health. Therefore, how to effectively improve and treat AD is an urgent problem. In this study, a novel multitarget derivative based on tacrine (named 9i), which could work simultaneously on more than one pathological target, was used to treat AD model APP/PSI transgenic mice. After 4 weeks of intragastric administration, cognitive function and synaptic plasticity were significantly improved and beta-amyloid (A beta) plaques that are main pathological hallmarks of AD were decreased in the APP/PS1 mice. On the one hand, 9i inhibited the excessive activation of the Raf/MEK/ERK signaling pathway to alleviate the loss of neurons, which provides a foundation for structural integrity. On the other hand, synaptic associated proteins and the density of synaptic spines were increased in APP/PSI mice treated with 9i, which provides the basis for the improvement of synaptic plasticity and cognitive impairment. Interestingly, 9i also reduced A beta plaques in the DG region, which is consistent with previous in vitro experiments showing that 9i inhibited the self-assembly of A beta fibers, thus protecting neurons from A beta plaque neurotoxicity. Our results suggest that 9i as a novel compound can effectively improve the cognitive function and the pathological changes of AD in APP/PS1 transgenic mice.