摘要
丝氨酸水解酶的丁酰胆碱酯酶(BChE),如相关的酶乙酰胆碱酯酶(AChE),共同调节神经递质乙酰胆碱的代谢。人类大脑中BChE主要在白质和神经胶质细胞里表达,也在阿尔茨海默病(AD)不同人群的被破坏的认知和行为功能的重要区域的神经元有表达。AD是一种导致老年痴呆症的神经退行性疾病,一生不能治愈,也没有明确的诊断手段。AD的病理与BChE相关,如β-淀粉样蛋白(Aβ)斑块,特别是在大脑皮层,通常找不到定量的BChE。高达30%的认知功能正常的老年人的大脑有丰富的Aβ沉积。我们设计了一种显像剂,通过放射自显影法,可以检测到AD患者的大脑皮质里BChE相关的Aβ斑块,但在认知正常的人的大脑里不显象Aβ斑块。此外,敲除BChE基因的AD小鼠模型,高达70%的大脑Aβ斑块纤维减少,建议减少BchE活性可以被证明是治疗AD的有益的方法。为此,我们已经研究了许多人类BChE的特有抑制剂N-10-羰基吩噻嗪类,揭示酶的活性位点要道的重要的细节。这些吩噻嗪类可被设计而没有神经递质受体的相互作用引起的副作用。总之,BChE可能是AD诊断和治疗的重要靶点。
关键词: 乙酰胆碱酯酶,淀粉样蛋白、胆碱能、痴呆、神经影像学、吩噻嗪类。
Current Alzheimer Research
Title:Butyrylcholinesterase as a Diagnostic and Therapeutic Target for Alzheimer’s Disease
Volume: 13 Issue: 10
Author(s): Sultan Darvesh
Affiliation:
关键词: 乙酰胆碱酯酶,淀粉样蛋白、胆碱能、痴呆、神经影像学、吩噻嗪类。
摘要: The serine hydrolase butyrylcholinesterase (BChE), like the related enzyme acetylcholinesterase (AChE), co-regulates metabolism of the neurotransmitter acetylcholine. In the human brain BChE is mainly expressed in white matter and glia and in distinct populations of neurons in regions that are important in cognition and behavior, functions compromised in Alzheimer’s disease (AD). AD is a neurodegenerative disorder causing dementia with no cure nor means for definitive diagnosis during life. In AD, BChE is found in association with pathology, such as β-amyloid (Aβ) plaques, particularly in the cerebral cortex where BChE is not normally found in quantity. Up to 30% of cognitively normal older adults have abundant Aβ deposition in the brain. We have designed an imaging agent that can detect, through autoradiography, BChE-associated Aβ plaques in the cerebral cortex of AD brains, but does not visualize Aβ plaques in brains of cognitively normal individuals. Furthermore, in an AD mouse model with BChE gene knocked out, there are up to 70% fewer fibrillar Aβ brain plaques, suggesting diminished BChE activity could prove beneficial as a curative approach to AD. To that end, we have examined numerous N-10-carbonyl phenothiazines that are specific inhibitors of human BChE, revealing important details of the enzyme’s active site gorge. These phenothiazines can be designed without potential side effects caused by neurotransmitter receptor interactions. In conclusion, BChE is potentially an important target for diagnosis and treatment of AD.
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Sultan Darvesh , Butyrylcholinesterase as a Diagnostic and Therapeutic Target for Alzheimer’s Disease, Current Alzheimer Research 2016; 13 (10) . https://dx.doi.org/10.2174/1567205013666160404120542
DOI https://dx.doi.org/10.2174/1567205013666160404120542 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
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