Inactivation of GAP-43 due to the depletion of cellular calcium by the Pb and amyloid peptide induced toxicity: An in vitro approach
Inactivation of GAP-43 due to the depletion of cellular calcium by the Pb and amyloid peptide induced toxicity: An in vitro approach
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DOI：
10.1016/j.cbi.2019.108927
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发表时间：
2020-01-25
影响因子：
5.1
通讯作者：
Challa, Suresh
中科院分区：
文献类型：
--
作者：
Ayyalasomayajula, Neelima;Bandaru, Madhuri;Challa, Suresh
已知环境污染物铅（Pb）对人体具有神经毒性。中枢神经系统最容易受到微量铅中毒的影响。铅作为一种可能的危险因素与阿尔茨海默病（AD）有关，因为它显示出与阿尔茨海默病样病理相关的表观遗传和发育联系。β淀粉样蛋白肽被认为是阿尔茨海默病大脑β淀粉样蛋白斑块形成的关键因素。在此背景下，我们在体外研究了铅诱导阿尔茨海默病发生的分子机制。我们先前的研究数据已经报道，与单独暴露相比，存在β淀粉样肽（1-40）和（25-35）的Pb诱导更多的细胞凋亡。本文进一步探讨铅诱发阿尔茨海默病的分子机制；我们关注钙信号在诱导细胞死亡中的作用。我们的实验结果表明，在β -淀粉样肽存在的情况下，铅会改变细胞内钙水平，从而导致β -分泌酶活性增加，从而进一步促进β -淀粉样肽的生成。它还显示GAP-43表达水平的抑制，PKC活性的抑制和突触活性的改变进一步导致细胞死亡。
Environmental pollutant, Lead (Pb) is known to induce neurotoxicity in human. The central nervous system is the most vulnerable to the minute levels of Pb induced toxicity. Pb has been linked to Alzheimer's disease (AD) as a probable risk factor, as it shows epigenetic and developmental link associated with Alzheimer's disease-like pathology. Beta amyloid peptides were considered as the crucial factors in the beta amyloid plaque formation in Alzheimer's disease brain. In this context, we investigated the molecular mechanism involved in the development of Pb induced Alzheimer's disease in in vitro. Previous data from our studies have reported that Pb in the presence of beta Amyloid peptide (1-40) and (25-35) induces more apoptosis than individual exposures. Here, to further evaluate the molecular mechanism underlying Pb induced Alzheimer's disease; we focussed on the involvement of calcium signalling in inducing cell death. Our experimental observations suggesting that Pb in the presence of beta amyloid peptide alters intracellular calcium levels, which leads to the increased beta-secretase activity, which further promotes the generation of beta amyloid peptides. It also showed depression in the levels of GAP-43 expression, inhibition of PKC activity and altering synaptic activity further leads to cell death.