Evaluations of the neuroprotective effects of a dual-target isoquinoline inhibitor in the triple transgenic mouse model of Alzheimer's disease. (1st April 2023)

• Record Type: Journal Article
• Authors: Wei, Rong; He, Jun-Qiu; Chen, Wen-Hua; Tam, Kin Yip
• Is Part Of: Neuroscience letters. Volume 802(2023)
• Publication Date: 2023-04-01
• Subjects: Alzheimer's disease -- Dual-target inhibitor -- Apoptosis -- Amyloid plaque -- Early stage disease; Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2023.137166
• Languages: English
• ISSNs: 0304-3940

Abstract

Graphical abstract: Highlights: The neuroprotective effects of 9S were studied in in vitro and in vivo models of AD. 9S exerted neuroprotective effects via modulation of neuronal apoptosis and GSK-3β. 9S enhanced acetylcholine level and reduced amyloid burden in brains of 3 × Tg AD mice. 9S not efficacious in older mice confirmed the treatment in early stage disease. Abstract: Alzheimer's disease (AD) patients exhibit neuropathological features, such as amyloid-beta (Aβ) 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 Aβ aggregation in in vitro and in vivo models of AD. 9S exhibited neuroprotective effects in Aβ-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-3β phosphorylation and reactive oxygen species. One-month administration of 9S to triple transgenic AD (3 × Tg-AD) female mice (aged 6 months) led to significant improvement in cognitive deficits. Whereas similar treatment regimens for older 3 × 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.