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An Isoquinolinium Dual Inhibitor of Cholinesterases and Amyloid β Aggregation Mitigates Neuropathological Changes in a Triple-Transgenic Mouse Model of Alzheimer's Disease
Ju,Yaojun; Chakravarty,Harapriya; Tam,Kin Yip
2020-10-21
Source PublicationACS Chemical Neuroscience
ISSN1948-7193
Volume11Issue:20Pages:3346-3357
Abstract

Alzheimer's disease (AD) is a complex neurodegenerative disorder affecting millions of people worldwide. The underlying pathologic mechanisms of AD are unclear. Over the decades, the development of single target agent did not lead to any successful treatment for AD. A multitarget agent that could tackle more than one AD phenotype may be helpful as a treatment strategy. Cholinesterases (ChEs) including acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), are currently the drug targets with approved treatments. Moreover, amyloid beta (Aβ) deposition is a hallmark of AD that receives considerable attention. Herein, 9Q, a previously reported dual target inhibitor dealing with cholinergic dysfunction and amyloid deposition for AD treatment, has undergone thorough investigations. In vitro studies revealed that 9Q exhibited over 80% inhibition of ChE activity at 100 μM and more than 30% inhibition of Aβ aggregation at 1 mM concentration. Moreover 9Q was able to penetrate the blood-brain barrier (BBB) and enhance the cerebral acetylcholine level in triple transgenic AD (3xTg-AD) mice. Following one month treatment with 9Q, the amyloid burden and the cognitive deficits in 3xTg-AD mice were significantly ameliorated. It was observed that 9Q treatment mitigated synapse dysfunction, decreased amyloidogenic APP processing, and reduced the tau pathology in 3xTg-AD mice. Taken together, our results suggested that dual inhibition of cholinesterases and Aβ aggregation could be a promising approach in AD treatment.

KeywordAlzheimer's Disease Amyloid Beta Cholinesterase Dual Inhibition
DOI10.1021/acschemneuro.0c00464
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaBiochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Neurosciences & Neurology
WOS SubjectBiochemistry & Molecular Biology ; Chemistry, Medicinal ; Neurosciences
WOS IDWOS:000584491300020
Scopus ID2-s2.0-85094219708
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Cited Times [WOS]:3   [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,Macao
First Author AffilicationFaculty of Health Sciences
Corresponding Author AffilicationFaculty of Health Sciences
Recommended Citation
GB/T 7714
Ju,Yaojun,Chakravarty,Harapriya,Tam,Kin Yip. An Isoquinolinium Dual Inhibitor of Cholinesterases and Amyloid β Aggregation Mitigates Neuropathological Changes in a Triple-Transgenic Mouse Model of Alzheimer's Disease[J]. ACS Chemical Neuroscience,2020,11(20):3346-3357.
APA Ju,Yaojun,Chakravarty,Harapriya,&Tam,Kin Yip.(2020).An Isoquinolinium Dual Inhibitor of Cholinesterases and Amyloid β Aggregation Mitigates Neuropathological Changes in a Triple-Transgenic Mouse Model of Alzheimer's Disease.ACS Chemical Neuroscience,11(20),3346-3357.
MLA Ju,Yaojun,et al."An Isoquinolinium Dual Inhibitor of Cholinesterases and Amyloid β Aggregation Mitigates Neuropathological Changes in a Triple-Transgenic Mouse Model of Alzheimer's Disease".ACS Chemical Neuroscience 11.20(2020):3346-3357.
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