Journal
NEUROSCIENCE LETTERS
Volume 802, Issue -, Pages -Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.neulet.2023.137166
Keywords
Alzheimer?s disease; Dual-target inhibitor; Apoptosis; Amyloid plaque; Early stage disease
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Alzheimer's disease (AD) patients exhibit neuropathological features, such as amyloid-beta (A beta) plaques and neurogenic fibrillary tangles. These features are thought to play important pathogenic roles in neuronal dysfunction and apoptosis in the disease progression. A dual-target isoquinoline inhibitor (9S) showed neuroprotective effects through modulations of GSK-3 beta phosphorylation and reactive oxygen species, leading to significant improvement in cognitive deficits in early-stage AD models.
Alzheimer's disease (AD) patients exhibit neuropathological features, such as amyloid-beta (A beta) 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 A beta aggregation in in vitro and in vivo models of AD. 9S exhibited neuroprotective effects in A beta-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-3 beta 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 ef-fects. These findings suggest the importance of therapeutic intervention at the early stage of the disease.
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