Novel small molecular compound 2JY-OBZ4 alleviates AD pathology in cell models via regulating multiple targets
AGING-US(2022)
摘要
Alzheimer's disease (AD) is the most common form of neurodegenerative dementia, characterized by cognitive deficits and memory dysfunction, which is clinically incurable so far. Novel small molecular compound 2JY-OBZ4 is one of structural analogue of Huperzine A (Hup-A), an anti-AD drug in China. In our previous work, 2JY-OBZ4 exhibited potent effects on tau hyperphosphorylation, A beta production and acetylcholinesterase (AChE) activity. However, 2JY-OBZ4's anti-AD effects and the underlying molecular mechanisms remain unclear. We here reported that 2JY-OBZ4 resisted tau hyperphosphorylation at Thr181 and Ser396 sites in HEK293-hTau cells transfected with GSK-3 beta, decreased tau phosphorylation via upregulating the activity of PP2A in HEK293-hTau cells and reduced A beta production through regulating protein levels of APP cleavage enzymes in N2a-hAPP cells. Meanwhile, we found that 2JY-OBZ4 had no adverse effects on cell viability of mice primary neuron even at high concentration, and ameliorated synaptic loss induced by human oligomeric A beta 42. 2JY-OBZ4 had moderate AChE inhibitory activity with the half maximal inhibitory concentration (IC50) to be 39.48 mu g/ml in vitro, which is more than two times higher than Hup-A. Together, 2JY-OBZ4 showed promising therapeutic effects in AD cell models through regulating multiple targets. The research provides a new candidate for the therapeutic development of AD.
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关键词
Alzheimer's disease (AD),Huperzine A (Hup-A),beta-secretase 1 (BACE1),protein phosphatase-2A (PP2A),cholinesterase inhibitor
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