Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells.
Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells.
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DOI：
10.1038/nature10821
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发表时间：
2012-01-25
期刊：
影响因子：
64.8
通讯作者：
Goldstein, Lawrence S. B.
中科院分区：
文献类型：
--
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.
目前，我们对阿尔茨海默病发病机制的了解受到从患者那里获得活神经元的困难以及无法对这种疾病的零星形式进行建模的限制。通过将患者的原代细胞重新编程为诱导多能干细胞(IPSCs)，可能有可能克服这些挑战。在这里，我们重新编程来自两个家族性阿尔茨海默病患者的原代成纤维细胞，这两个患者都是由淀粉样蛋白前体蛋白基因(APP；称为APPDP)重复引起的，两个散发性阿尔茨海默病患者(称为SAD1SAD2)和两个非痴呆对照个体被重新编程为IPSC系。用荧光激活细胞分选法对分化后的神经细胞进行纯化和鉴定。纯化的培养物含有90%以上的神经元，与基因芯片标准的胎儿脑信使RNA样本聚集在一起，可以形成功能性突触接触。几乎所有细胞都表现出正常的电生理活动。与对照组相比，来自两个APPDP患者和患者SAD2的IPSC来源的纯化神经元的病理标记物淀粉样蛋白β(1-40)、磷酸化tau(Thr231)和活性糖原合成酶-3β(aGSK-3β)水平显著升高。与对照组相比，APPDp和sAD2患者的神经元也积累了大量RAB5阳性的早期内体。用β分泌酶抑制剂处理纯化的神经元，但不用γ分泌酶抑制剂处理，可显著降低磷酸化Tau(Thr231)和aGSK-3β水平。这些结果表明，在人类神经元中，APP蛋白分解过程而不是淀粉样蛋白-β激活GSK-3β和tau磷酸化之间存在直接关系。此外，我们观察到具有一名SAD患者基因组的神经元表现出在家族性阿尔茨海默病样本中看到的表型。更广泛地说，我们证明了IPSC技术可以用来观察与阿尔茨海默病相关的表型，尽管显性疾病在患者身上可能需要几十年的时间才能显现。
Our understanding of Alzheimer’s disease pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of the disease. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). Here we reprogrammed primary fibroblasts from two patients with familial Alzheimer’s disease, both caused by a duplication of the amyloid-β precursor protein gene (APP; termed APPDp), two with sporadic Alzheimer’s disease (termed sAD1, sAD2) and two non-demented control individuals into iPSC lines. Neurons from differentiated cultures were purified with fluorescence-activated cell sorting and characterized. Purified cultures contained more than 90% neurons, clustered with fetal brain messenger RNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APPDp patients and patient sAD2 exhibited significantly higher levels of the pathological markers amyloid-β(1–40), phospho-tau(Thr 231) and active glycogen synthase kinase-3β (aGSK-3β). Neurons from APPDp and sAD2 patients also accumulated large RAB5-positive early endosomes compared to controls. Treatment of purified neurons with β-secretase inhibitors, but not γ-secretase inhibitors, caused significant reductions in phospho-Tau(Thr 231) and aGSK-3β levels. These results suggest a direct relationship between APP proteolytic processing, but not amyloid-β, in GSK-3β activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial Alzheimer’s disease samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to Alzheimer’s disease, even though it can take decades for overt disease to manifest in patients.
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影响因子：
3.7
作者：
Emre N;Vidal JG;Elia J;O'Connor ED;Paramban RI;Hefferan MP;Navarro R;Goldberg DS;Varki NM;Marsala M;Carson CT
通讯作者：
Carson CT
影响因子：
11.2
作者：
Cataldo, A;Rebeck, GW;Nixon, R
通讯作者：
Nixon, R
DOI：
10.1073/pnas.0908953107
发表时间：
2010-01-26
影响因子：
11.1
作者：
Jiang, Ying;Mullaney, Kerry A.;Nixon, Ralph A.
通讯作者：
Nixon, Ralph A.
影响因子：
4.8
作者：
Cho, JH;Johnson, GVW
通讯作者：
Johnson, GVW
影响因子：
14.8
作者：
Park, In-Hyun;Lerou, Paul H.;Daley, George Q.
通讯作者：
Daley, George Q.