Subtype-specific neurons from patient iPSCs display distinct neuropathological features of Alzheimer's disease.

IF 4 Q2 CELL & TISSUE ENGINEERING
Ran Tao, Chunmei Yue, Zhijie Guo, Wenke Guo, Yao Yao, Xianfa Yang, Zhen Shao, Chao Gao, Jianqing Ding, Lu Shen, Shengdi Chen, Naihe Jing
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Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by massive neuronal loss in the brain. Both cortical glutamatergic neurons and basal forebrain cholinergic neurons (BFCNs) in the AD brain are selectively vulnerable. The degeneration and dysfunction of these two subtypes of neurons are closely associated with the cognitive decline of AD patients. The determination of cellular and molecular mechanisms involved in AD pathogenesis, especially in the early stage, will largely facilitate the understanding of this disease and the development of proper intervention strategies. However, due to the inaccessibility of living neurons in the brains of patients, it remains unclear how cortical glutamatergic neurons and BFCNs respond to pathological stress in the early stage of AD. In this study, we established in vitro differentiation systems that can efficiently differentiate patient-derived iPSCs into BFCNs. We found that AD-BFCNs secreted less Aβ peptide than cortical glutamatergic neurons did, even though the Aβ42/Aβ40 ratio was comparable to that of cortical glutamatergic neurons. To further mimic the neurotoxic niche in AD brain, we treated iPSC-derived neurons with Aβ42 oligomer (AβO). BFCNs are less sensitive to AβO induced tau phosphorylation and expression than cortical glutamatergic neurons. However, AβO could trigger apoptosis in both AD-cortical glutamatergic neurons and AD-BFCNs. In addition, AD iPSC-derived BFCNs and cortical glutamatergic neurons exhibited distinct electrophysiological firing patterns and elicited different responses to AβO treatment. These observations revealed that subtype-specific neurons display distinct neuropathological changes during the progression of AD, which might help to understand AD pathogenesis at the cellular level.

来自患者 iPSCs 的亚型特异性神经元显示出阿尔茨海默病的不同神经病理学特征。
阿尔茨海默病(AD)是一种进行性神经退行性疾病,以大脑神经元大量丧失为特征。阿尔茨海默病大脑中的皮质谷氨酸能神经元和基底前脑胆碱能神经元(BFCNs)都是选择性易损的。这两种亚型神经元的退化和功能障碍与 AD 患者的认知能力下降密切相关。确定参与注意力缺失症发病机制的细胞和分子机制,尤其是在早期阶段,将在很大程度上促进对该疾病的理解和制定适当的干预策略。然而,由于无法获得患者大脑中的活体神经元,目前仍不清楚 AD 早期皮质谷氨酸能神经元和 BFCN 对病理应激的反应。在本研究中,我们建立了体外分化系统,该系统可将源自患者的 iPSCs 高效分化为 BFCNs。我们发现,AD-BFCNs分泌的Aβ肽少于皮质谷氨酸能神经元,即使Aβ42/Aβ40比率与皮质谷氨酸能神经元相当。为了进一步模拟 AD 大脑中的神经毒性生态位,我们用 Aβ42 寡聚体(AβO)处理 iPSC 衍生的神经元。与大脑皮层谷氨酸能神经元相比,BFCNs 对 AβO 诱导的 tau 磷酸化和表达的敏感性较低。然而,AβO可引发AD皮质谷氨酸能神经元和AD-BFCNs的细胞凋亡。此外,AD iPSC衍生的BFCNs和皮质谷氨酸能神经元表现出不同的电生理发射模式,并对AβO处理产生不同的反应。这些观察结果表明,亚型特异性神经元在AD进展过程中表现出不同的神经病理学变化,这可能有助于从细胞水平了解AD的发病机制。
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来源期刊
Cell Regeneration
Cell Regeneration Biochemistry, Genetics and Molecular Biology-Cell Biology
CiteScore
5.80
自引率
0.00%
发文量
42
审稿时长
35 days
期刊介绍: Cell Regeneration aims to provide a worldwide platform for researches on stem cells and regenerative biology to develop basic science and to foster its clinical translation in medicine. Cell Regeneration welcomes reports on novel discoveries, theories, methods, technologies, and products in the field of stem cells and regenerative research, the journal is interested, but not limited to the following topics: ◎ Embryonic stem cells ◎ Induced pluripotent stem cells ◎ Tissue-specific stem cells ◎ Tissue or organ regeneration ◎ Methodology ◎ Biomaterials and regeneration ◎ Clinical translation or application in medicine
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