Tao Ran, Yue Chunmei, Guo Zhijie, Guo Wenke, Yao Yao, Yang Xianfa, Shao Zhen, Gao Chao, Ding Jianqing, Shen Lu, Chen Shengdi, Jing Naihe
Guangzhou National Laboratory, Guangzhou International Bio Island, No. 9 Xing Dao Huan Bei Road, Guangdong Province, 510005, China.
Suzhou Yuanzhan Biotechs, Suzhou, 215000, China.
Cell Regen. 2024 Oct 10;13(1):21. doi: 10.1186/s13619-024-00204-y.
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.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征是大脑中大量神经元丢失。AD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）均具有选择性易损性。这两种神经元亚型的退化和功能障碍与AD患者的认知衰退密切相关。确定AD发病机制中所涉及的细胞和分子机制，尤其是在疾病早期阶段，将在很大程度上有助于对该疾病的理解以及制定适当的干预策略。然而，由于无法获取患者大脑中的活神经元，目前尚不清楚皮质谷氨酸能神经元和BFCNs在AD早期阶段如何应对病理应激。在本研究中，我们建立了体外分化系统，该系统能够有效地将患者来源的诱导多能干细胞（iPSCs）分化为BFCNs。我们发现，AD-BFCNs分泌的Aβ肽比皮质谷氨酸能神经元少，尽管Aβ42/Aβ40比值与皮质谷氨酸能神经元相当。为了进一步模拟AD大脑中的神经毒性微环境，我们用Aβ42寡聚体（AβO）处理iPSC衍生的神经元。BFCNs对AβO诱导的tau蛋白磷酸化和表达的敏感性低于皮质谷氨酸能神经元。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放电模式，并且对AβO处理产生不同的反应。这些观察结果表明，在AD进展过程中，亚型特异性神经元表现出不同的神经病理变化，这可能有助于在细胞水平上理解AD的发病机制。
