Rivastigmine lowers Aβ and increases sAPPα levels, which parallel elevated synaptic markers and metabolic activity in degenerating primary rat neurons.
Rivastigmine lowers Aβ and increases sAPPα levels, which parallel elevated synaptic markers and metabolic activity in degenerating primary rat neurons.
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DOI：
10.1371/journal.pone.0021954
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Lahiri DK
中科院分区：
文献类型：
--
作者：
Bailey JA;Ray B;Greig NH;Lahiri DK
脑中淀粉样蛋白-β（Aβ）的过度产生已被假设为主要毒性损伤，其通过多种机制产生阿尔茨海默病（AD）中的认知缺陷。胆碱酯酶抑制是治疗AD的主要策略，并且先前已证明该类特定化合物影响Aβ前体蛋白（APP）加工和Aβ产生。然而，关于卡巴拉汀（一种双重乙酰胆碱酯酶和丁酰胆碱酯酶抑制剂）对APP加工的影响的信息很少。由于该药物目前用于治疗AD，因此其各种活性的表征对于优化其临床效用非常重要。我们之前已经证明，rivastigmine可以保留或增强退化的原代胚胎皮质培养物中的神经元和突触终末标记。鉴于先前关于APP和Aβ对突触影响的报告，APP加工的调节代表了rivastigmine突触作用的合理机制。为了检验这一假设，我们用卡巴拉汀处理退化的原代培养物，并测量分泌的APP（sAPP）和Aβ。卡巴拉汀处理增加了这些培养细胞的代谢活性，并增加了APP分泌。基于分子量，对这些培养物分泌的两种主要形式的APP（归因于神经元或神经胶质）进行分析，结果表明，相对于神经胶质分泌的APP，利斯的明给药显著增加了神经元分泌的APP。此外，利斯的明给药增加了α-分泌酶切割的sAPPα，并减少了Aβ分泌，表明利斯的明改变了分泌酶途径的相对活性的治疗机制。rivastigmine每日一次给药21天后，啮齿动物CSF中sAPP水平的评估证实了细胞培养物中APP水平升高在体内转化。总之，rivastigmine给药可增强神经元sAPP，并将APP加工转移至退化神经元培养物中的α-分泌酶途径，这反映了突触蛋白和代谢活性的趋势。
Overproduction of amyloid-β (Aβ) protein in the brain has been hypothesized as the primary toxic insult that, via numerous mechanisms, produces cognitive deficits in Alzheimer's disease (AD). Cholinesterase inhibition is a primary strategy for treatment of AD, and specific compounds of this class have previously been demonstrated to influence Aβ precursor protein (APP) processing and Aβ production. However, little information is available on the effects of rivastigmine, a dual acetylcholinesterase and butyrylcholinesterase inhibitor, on APP processing. As this drug is currently used to treat AD, characterization of its various activities is important to optimize its clinical utility. We have previously shown that rivastigmine can preserve or enhance neuronal and synaptic terminal markers in degenerating primary embryonic cerebrocortical cultures. Given previous reports on the effects of APP and Aβ on synapses, regulation of APP processing represents a plausible mechanism for the synaptic effects of rivastigmine. To test this hypothesis, we treated degenerating primary cultures with rivastigmine and measured secreted APP (sAPP) and Aβ. Rivastigmine treatment increased metabolic activity in these cultured cells, and elevated APP secretion. Analysis of the two major forms of APP secreted by these cultures, attributed to neurons or glia based on molecular weight showed that rivastigmine treatment significantly increased neuronal relative to glial secreted APP. Furthermore, rivastigmine treatment increased α-secretase cleaved sAPPα and decreased Aβ secretion, suggesting a therapeutic mechanism wherein rivastigmine alters the relative activities of the secretase pathways. Assessment of sAPP levels in rodent CSF following once daily rivastigmine administration for 21 days confirmed that elevated levels of APP in cell culture translated in vivo. Taken together, rivastigmine treatment enhances neuronal sAPP and shifts APP processing toward the α-secretase pathway in degenerating neuronal cultures, which mirrors the trend of synaptic proteins, and metabolic activity.
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影响因子：
4.2
作者：
Alley, George M.;Bailey, Jason A.;Chen, DeMao;Ran, Balmiki;Puli, Lakshman K.;Tanila, Heikki;Banerjee, Pradeep K.;Lahiri, Debomoy K.
通讯作者：
Lahiri, Debomoy K.
影响因子：
5.3
作者：
Hayashi, H;Kimura, N;Yanagisawa, K
通讯作者：
Yanagisawa, K
影响因子：
3.4
作者：
Kadir, Ahmadul;Darreh-Shori, Taher;Nordberg, Agneta
通讯作者：
Nordberg, Agneta
影响因子：
3.9
作者：
Lahiri, Debomoy K.;Maloney, Bryan
通讯作者：
Maloney, Bryan
影响因子：
4.8
作者：
Gralle, Matthias;Botelho, Michelle Gralle;Wouters, Fred S.
通讯作者：
Wouters, Fred S.