Mak S

References (4)

Title : Regulation of acetylcholinesterase during the lipopolysaccharide-induced inflammatory responses in microglial cells - Xia_2022_FASEB.J_36_e22189
Author(s) : Xia Y , Wu Q , Mak S , Liu EYL , Zheng BZY , Dong TTX , Pi R , Tsim KWK
Ref : FASEB Journal , 36 :e22189 , 2022
Abstract : The non-classical function of acetylcholine (ACh) has been reported in neuroinflammation that represents the modulating factor in immune responses via activation of alpha7 nicotinic acetylcholine receptor (alpha7 nAChR), i.e., a cholinergic anti-inflammatory pathway (CAP). Acetylcholinesterase (AChE), an enzyme for ACh hydrolysis, has been proposed to have a non-classical function in immune cells. However, the involvement of AChE in neuroinflammation is unclear. Here, cultured BV2 cell, a microglial cell line, and primary microglia from rats were treated with lipopolysaccharide (LPS) to induce inflammation and to explore the regulation of AChE during this process. The expression profiles of AChE, alpha7 nAChR, and choline acetyltransferase (ChAT) were revealed in BV2 cells. The expression of AChE (G4 form) was induced significantly in LPS-treated BV2 cells: the induction was triggered by NF-kappaB and cAMP signaling. Moreover, ACh or alpha7 nAChR agonist suppressed the LPS-induced production of pro-inflammatory cytokines, as well as the phagocytosis of microglia, by activating alpha7 nAChR and followed by the regulation of NF-kappaB and CREB signaling. The ACh-induced suppression of inflammation was abolished in AChE overexpressed cells, but did not show a significant change in AChE mutant (enzymatic activity knockout) transfected cells. These results indicate that the neuroinflammation-regulated function of AChE may be mediated by controlling the ACh level in the brain system.
ESTHER : Xia_2022_FASEB.J_36_e22189
PubMedSearch : Xia_2022_FASEB.J_36_e22189
PubMedID: 35129858

Title : Promising tacrine\/huperzine A-based dimeric acetylcholinesterase inhibitors for neurodegenerative disorders: From relieving symptoms to modifying diseases through multitarget - Mak_2021_J.Neurochem__
Author(s) : Mak S , Li W , Fu H , Luo J , Cui W , Hu S , Pang Y , Carlier PR , Tsim KWK , Pi R , Han Y
Ref : Journal of Neurochemistry , : , 2021
Abstract : Neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, are devastating diseases in the elderly world, which are closely associated with progressive neuronal loss induced by a variety of genetic and/or environmental factors. Unfortunately, currently available treatments for neurodegenerative disorders can only relieve the symptoms but not modify the pathological processes. Over the past decades, our group by collaborating with Profs. Yuan-Ping Pang and Paul R. Carlier has developed three series of homo/hetero dimeric acetylcholinesterase inhibitors derived from tacrine and/or huperzine A. The representative dimers bis(3)-Cognitin (B3C), bis(12)-hupyridone, and tacrine(10)-hupyridone might possess disease-modifying effects through the modulation of N-methyl-d-aspartic acid receptors, the activation of myocyte enhancer factor 2D gene transcription, and the promotion of neurotrophic factor secretion. In this review, we summarize that the representative dimers, such as B3C, provide neuroprotection against a variety of neurotoxins via multiple targets, including the inhibitions of N-methyl-d-aspartic acid receptor with pathological-activated potential, neuronal nitric oxide synthase, and beta-amyloid cascades synergistically. More importantly, B3C might offer disease-modifying potentials by activating myocyte enhancer factor 2D transcription, inducing neuritogenesis, and promoting the expressions of neurotrophic factors in vitro and in vivo. Taken together, the novel dimers might offer synergistic disease-modifying effects, proving that dimerization might serve as one of the strategies to develop new generation of therapeutics for neurodegenerative disorders.
ESTHER : Mak_2021_J.Neurochem__
PubMedSearch : Mak_2021_J.Neurochem__
PubMedID: 33930191

Title : Tacrine induces endoplasmic reticulum-stressed apoptosis via disrupting the proper assembly of oligomeric acetylcholinesterase in cultured neuronal cells - Liu_2021_Mol.Pharmacol__
Author(s) : Liu EYL , Mak S , Kong X , Xia Y , Kwan KKL , Xu ML , Tsim KWK
Ref : Molecular Pharmacology , : , 2021
Abstract : Acetylcholinesterase inhibitors (AChEIs), the most developed treatment strategies for Alzheimer's disease (AD), will be used in clinic for, at least, the next decades. Their side effects are in highly variable from drug to drug whose mechanism remain to be fully established. The withdrawal of tacrine (Cognex(a)) in the market makes it as an interesting case study. Here, we found tacrine could disrupt the proper trafficking of proline-rich membrane anchor-linked tetrameric AChE in the endoplasmic reticulum (ER). The exposure of tacrine in cells expressing AChE, e.g. neuron, caused an accumulation of the misfolded AChE in the ER. This misfolded enzyme was not able to transport to Golgi/plasma membrane, which subsequently induced ER stress and its downstream signaling cascade of unfolded protein response (UPR). Once the stress was overwhelming, the cooperation of ER with mitochondria increased the loss of mitochondrial membrane potential. Eventually, the tacrine-exposed cells lost homeostasis and undergone apoptosis. The ER stress and apoptosis, induced by tacrine, were proportional to the amount of AChE. Other AChEIs (rivastigmine, bis(3)-cognitin, daurisoline and dauricine) could cause the same problem as tacrine by inducing ER stress in neuronal cells. The results provide guidance for the drug design and discovery of AChEIs for AD treatment. Significance Statement AChEIs are the most developed treatment strategies for Alzheimer's disease (AD) and will be used in clinic for at least the next decades. Our study reports tacrine and other AChEIs disrupt the proper trafficking of AChE in the endoplasmic reticulum. Eventually, the apoptosis of neurons and other cells are induced. The results provide guidance for drug design and discovery of AChEIs for AD treatment.
ESTHER : Liu_2021_Mol.Pharmacol__
PubMedSearch : Liu_2021_Mol.Pharmacol__
PubMedID: 34531295

Title : Interacting with alpha 7 nAChR is a new mechanism for AChE to enhance the inflammatory response in macrophages - Liu_2020_Acta.Pharm.Sin.B_10_1926
Author(s) : Liu EYL , Xia Y , Kong X , Guo MSS , Yu AXD , Zheng BZY , Mak S , Xu ML , Tsim KWK
Ref : Acta Pharm Sin B , 10 :1926 , 2020
Abstract : Acetylcholine (ACh) regulates inflammation via alpha7 nicotinic acetylcholine receptor (alpha7 nAChR). Acetylcholinesterase (AChE), an enzyme hydrolyzing ACh, is expressed in immune cells suggesting non-classical function in inflammatory responses. Here, the expression of PRiMA-linked G4 AChE was identified on the surface of macrophages. In lipopolysaccharide-induced inflammatory processes, AChE was upregulated by the binding of NF-kappaB onto the ACHE promotor. Conversely, the overexpression of G4 AChE inhibited ACh-suppressed cytokine release and cell migration, which was in contrast to that of applied AChE inhibitors. AChEmt, a DNA construct without enzymatic activity, was adopted to identify the protein role of AChE in immune system. Overexpression of G4 AChEmt induced cell migration and inhibited ACh-suppressed cell migration. The co-localization of alpha7 nAChR and AChE was found in macrophages, suggesting the potential interaction of alpha7 nAChR and AChE. Besides, immunoprecipitation showed a close association of alpha7 nAChR and AChE protein in cell membrane. Hence, the novel function of AChE in macrophage by interacting with alpha7 nAChR was determined. Together with hydrolysis of ACh, AChE plays a direct role in the regulation of inflammatory response. As such, AChE could serve as a novel target to treat age-related diseases by anti-inflammatory responses.
ESTHER : Liu_2020_Acta.Pharm.Sin.B_10_1926
PubMedSearch : Liu_2020_Acta.Pharm.Sin.B_10_1926
PubMedID: 33163344