Stem cell derived basal forebrain cholinergic neurons from Alzheimer's disease patients are more susceptible to cell death.
Stem cell derived basal forebrain cholinergic neurons from Alzheimer's disease patients are more susceptible to cell death.
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DOI：
10.1186/1750-1326-9-3
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发表时间：
2014-01-08
影响因子：
15.1
通讯作者：
Kessler JA
中科院分区：
文献类型：
--
作者：
Duan L;Bhattacharyya BJ;Belmadani A;Pan L;Miller RJ;Kessler JA
基底前脑胆碱能神经元 (BFCN) 的早期大量丧失是阿尔茨海默病 (AD) 的一个持续特征，并且与空间学习和记忆缺陷相关。来自 AD 患者和正常对照的诱导多能干细胞 (iPSC) 可以有效分化为具有 BFCN 特征的神经元。我们使用源自 iPSC 的 BFCN 来模拟散发性 AD，重点关注 ApoE3/E4 基因型 (AD-E3/E4) 的患者。来自 AD-E3/E4 患者的 BFCN 显示出典型的 AD 生化特征，表现为 Aβ42/Aβ40 比率增加。与对照 BFCN 或来自家族性 AD 患者的神经元相比，AD-E3/E4 神经元对 γ-分泌酶抑制剂治疗的反应也表现出改变。 AD-E3/E4 患者的 BFCN 也表现出对谷氨酸介导的细胞死亡的脆弱性增加，这与谷氨酸暴露后细胞内游离钙的增加相关。产生具有 AD 表型的 BFCN 的能力对于理解疾病机制和促进筛选促进突触完整性和神经元存活的药物来说是重要的一步。
An early substantial loss of basal forebrain cholinergic neurons (BFCNs) is a constant feature of Alzheimer’s disease (AD) and is associated with deficits in spatial learning and memory. Induced pluripotent stem cells (iPSCs) derived from patients with AD as well as from normal controls could be efficiently differentiated into neurons with characteristics of BFCNs. We used BFCNs derived from iPSCs to model sporadic AD with a focus on patients with ApoE3/E4 genotypes (AD-E3/E4). BFCNs derived from AD-E3/E4 patients showed typical AD biochemical features evidenced by increased Aβ42/Aβ40 ratios. AD-E3/E4 neurons also exhibited altered responses to treatment with γ-secretase inhibitors compared to control BFCNs or neurons derived from patients with familial AD. BFCNs from patients with AD-E3/E4 also exhibited increased vulnerability to glutamate-mediated cell death which correlated with increased intracellular free calcium upon glutamate exposure. The ability to generate BFCNs with an AD phenotype is a significant step both for understanding disease mechanisms and for facilitating screening for agents that promote synaptic integrity and neuronal survival.
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影响因子：
16.2
作者：
Kim, Jungsu;Basak, Jacob M.;Holtzman, David M.
通讯作者：
Holtzman, David M.
影响因子：
46.9
作者：
通讯作者：
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影响因子：
64.8
作者：
Israel, Mason A.;Yuan, Shauna H.;Bardy, Cedric;Reyna, Sol M.;Mu, Yangling;Herrera, Cheryl;Hefferan, Michael P.;Van Gorp, Sebastiaan;Nazor, Kristopher L.;Boscolo, Francesca S.;Carson, Christian T.;Laurent, Louise C.;Marsala, Martin;Gage, Fred H.;Remes, Anne M.;Koo, Edward H.;Goldstein, Lawrence S. B.
通讯作者：
Goldstein, Lawrence S. B.
影响因子：
9
作者：
通讯作者：
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DOI：
10.1523/jneurosci.0307-10.2010
发表时间：
2010-03-17
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Faedo A;Borello U;Rubenstein JL
通讯作者：
Rubenstein JL