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9R, the cholinesterase and amyloid beta aggregation dual inhibitor, as a multifunctional agent to improve cognitive deficit and neuropathology in the triple-transgenic Alzheimer's disease mouse model
Ju,Yaojun; Tam,Kin Yip
2020-12-15
Source PublicationNeuropharmacology
ISSN0028-3908
Volume181
Abstract

Alzheimer's disease (AD) is the most common kind of dementia in the aging population leading to great social and financial burdens in many countries around the world. For decades, disease-modifying drug developed using the “one target, one drug” strategy failed to conquer this disease. Recently, we have designed and synthesized 9R, which exhibited dual inhibition of cholinesterase and amyloid beta (Aβ) aggregation in vitro. Herein, we evaluated the in vivo efficacy of 9R in a triple transgenic AD (3xTg-AD) mouse model. 3xTg-AD mice (10-month-old) were dosed intraperitoneally with 9R (daily 3, 10 or 30 mg/kg) for a month. Known cholinesterase inhibitor donepezil (0.3 mg/kg) and Aβ aggregation inhibitor tramiprosate (30 mg/kg) were used as positive controls. Cognitive performance of the mice was then evaluated by using Morris Water Maze (MWM), Y-maze tasks and Open Field test. The acetylcholine level, degree of Aβ deposition, amyloid precursor protein (APP) processing, neuroinflammation, tau deposition and tau hyperphosphorylation in the brains of the 3xTg-AD mice were examined. We have observed that one-month treatment with 9R significantly improved cognitive deficits in 3xTg-AD mice. Moreover, 9R treatment enhanced the brain acetylcholine level and mitigated the amyloid burden, tau hyperphosphorylation and neuroinflammation in the mouse brains. The effects of 9R on APP processing, neuroinflammation, tau hyperphosphorylation and Cdk-p25 action demonstrated its multifunctional role in 3xTg-AD mouse model. Our results suggested that the use of multi-target compound could be a potential approach to treat AD.

KeywordAlzheimer's Disease Amyloid Beta Cholinesterase Dual Inhibition Multifunction
DOI10.1016/j.neuropharm.2020.108354
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaNeurosciences & Neurology ; Pharmacology & Pharmacy
WOS SubjectNeurosciences ; Pharmacology & Pharmacy
WOS IDWOS:000645153700001
Scopus ID2-s2.0-85092890545
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Cited Times [WOS]:5   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorTam,Kin Yip
AffiliationFaculty of Health Sciences,University of Macau,Avenida de Universidade,Taipa,Macao
First Author AffilicationFaculty of Health Sciences
Corresponding Author AffilicationFaculty of Health Sciences
Recommended Citation
GB/T 7714
Ju,Yaojun,Tam,Kin Yip. 9R, the cholinesterase and amyloid beta aggregation dual inhibitor, as a multifunctional agent to improve cognitive deficit and neuropathology in the triple-transgenic Alzheimer's disease mouse model[J]. Neuropharmacology,2020,181.
APA Ju,Yaojun,&Tam,Kin Yip.(2020).9R, the cholinesterase and amyloid beta aggregation dual inhibitor, as a multifunctional agent to improve cognitive deficit and neuropathology in the triple-transgenic Alzheimer's disease mouse model.Neuropharmacology,181.
MLA Ju,Yaojun,et al."9R, the cholinesterase and amyloid beta aggregation dual inhibitor, as a multifunctional agent to improve cognitive deficit and neuropathology in the triple-transgenic Alzheimer's disease mouse model".Neuropharmacology 181(2020).
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