Wei_2023_Neurosci.Lett_802_137166

Alzheimer's disease (AD) patients exhibit neuropathological features, such as amyloid-beta (Abeta) plaques and neurogenic fibrillary tangles. These features are thought to play important pathogenic roles, including neuronal dysfunction and apoptosis in the disease progression. Herein, we systematically evaluated a previously reported dual-target isoquinoline inhibitor (9S) for cholinesterase and Abeta aggregation in in vitro and in vivo models of AD. 9S exhibited neuroprotective effects in Abeta-induced and PHF6-induced PC12 cell models as well as in an okadaic acid-induced SH-SY5Y cell model, which were due to attenuated neuronal apoptosis through modulations of GSK-3beta phosphorylation and reactive oxygen species. One-month administration of 9S to triple transgenic AD (3 x Tg-AD) female mice (aged 6 months) led to significant improvement in cognitive deficits. Whereas similar treatment regimens for older 3 x Tg-AD female mice (aged 10 months) showed negligible neuroprotective effects. These findings suggest the importance of therapeutic intervention at the early stage of the disease.