Lahiri D K, Farlow M R, Hintz N, Utsuki T, Greig N H
Department of Psychiatry, Indiana University School of Medicine, Indianapolis 46202, USA.
Acta Neurol Scand Suppl. 2000;176:60-7. doi: 10.1034/j.1600-0404.2000.00309.x.
The extracellular deposition of amyloid beta-peptide (Abeta) in the form of cerebrovascular amyloid and extracellular plaques is one of the major neuropathological manifestations of Alzheimer's disease (AD). Abeta is generated proteolytically from the large beta-amyloid precursor protein (APP). APP is cleaved by a group of proteases called "secretase" to generate soluble derivatives of APP (sAPP), which are secreted in human plasma, CSF and cultured cells. Neurochemically, there is a severe loss of cholinergic neurons and a decreased synthesis of acetylcholine in neocortex in AD. Current approved AD drugs, such as aricept and tacrine, are based on the use of cholinesterase inhibitors (ChEIs) and have been reported to improve memory deficits and cognitive decline in some patients with AD. To compare the effects of ChEIs on APP processing, we have tested a series of ChEIs such as tacrine, physostigmine, metrifonate, phenserine and cymserine in cultured human neuroblastoma cells. We analyzed levels of sAPP by immunochemical techniques with APP-specific antibodies and assayed levels of Abeta by a sensitive sandwich ELISA. Based on these results, ChEIs can be divided into three groups: the first group of ChEIs had no effect on sAPP secretion, the second decreased the sAPP secretion only, and third group affected the secretion of sAPP and Abeta. The difference in the action of metrifonate, physostigmine, phenserine and tacrine on APP processing is independent of their selectivity for the cholinesterase enzymes. This possibly is due to the different targets that are used by ChEIs. Studying the effects of ChEIs on different targets is useful to maximize the benefit of ChEIs for the treatment of AD subjects.
β-淀粉样肽（Aβ）以脑血管淀粉样蛋白和细胞外斑块的形式在细胞外沉积，是阿尔茨海默病（AD）的主要神经病理学表现之一。Aβ是由大型β-淀粉样前体蛋白（APP）通过蛋白水解产生的。APP被一组称为“分泌酶”的蛋白酶切割，产生APP的可溶性衍生物（sAPP），这些衍生物分泌于人血浆、脑脊液和培养细胞中。在神经化学方面，AD患者新皮质中的胆碱能神经元严重丧失，乙酰胆碱合成减少。目前已获批的AD药物，如安理申和他克林，基于使用胆碱酯酶抑制剂（ChEIs），并且据报道在一些AD患者中可改善记忆缺陷和认知衰退。为了比较ChEIs对APP加工的影响，我们在培养的人神经母细胞瘤细胞中测试了一系列ChEIs，如他克林、毒扁豆碱、美曲膦酯、苯丝氨酸和环丝氨酸。我们用APP特异性抗体通过免疫化学技术分析sAPP水平，并通过灵敏的夹心ELISA测定Aβ水平。基于这些结果，ChEIs可分为三组：第一组ChEIs对sAPP分泌无影响，第二组仅降低sAPP分泌，第三组影响sAPP和Aβ的分泌。美曲膦酯、毒扁豆碱、苯丝氨酸和他克林对APP加工作用的差异与其对胆碱酯酶的选择性无关。这可能是由于ChEIs使用的靶点不同。研究ChEIs对不同靶点的影响有助于最大限度地提高ChEIs治疗AD患者的益处。
