Study on multi-target effects of PIMPC on Aβ/Cu²⁺-induced Alzheimer's disease model of rats

Glycogen synthase kinase-3 (GSK-3), a key role in the pathogenesis of Alzheimer's disease (AD), has been linked with the formation of β-amyloid (Aβ), tubulin-associated unit (tau) protein phosphorylation and apoptosis. Moreover, the excessive presence of elements such as copper (Cu) can promote Aβ aggregation and increase the risk of AD. Combined with the role of GSK-3 and metal elements in AD, a metal-chelating imine GSK-3 inhibitor N-(4-{[(2-amino-5-phenylpyridin-3-ylidene)imino]methyl}pyridin-2-yl)cyclopropanecarboxamide (PIMPC) was designed and synthesized. In our study, Aβ/Cu²⁺-induced AD rat model was established and treated with PIMPC. The results indicated that PIMPC can not only down-regulate the high expression levels of Aβ, tau and p-tau proteins of the AD rats, but also chelate Cu and aluminum (Al) elements in the brain. In addition, PIMPC may play an anti-apoptotic effect by down-regulating the high expression of cleaved Caspase-3 protein, and it can modulate ATPase and nitric oxide synthase (NOS) levels, oxidative stress and neurotransmitter disturbance. In summary, PIMPC acts on multiple targets to relieve the learning and memory impairment of AD rats induced by Aβ/Cu²⁺.