German Center for Neurodegenerative Diseases (DZNE) Dresden, Helmholtz Association, Arnoldstr. 18, 01307 Dresden, Germany; Center for Regenerative Therapies (CRTD), Technische Universität Dresden, Fetscherstr. 105, 01307 Dresden, Germany.
Leibniz Institute of Polymer Research Dresden, Max Bergmann Center of Biomaterials Dresden, Hohe Str. 6, 01069 Dresden, Germany; Institute of Health Biomedical Innovation (IHBI), Queensland University of Technology, 60 Musk Avenue, Kelvin Grove 4059, Australia.
Dev Cell. 2018 Jul 2;46(1):85-101.e8. doi: 10.1016/j.devcel.2018.06.005.
Neural stem cells (NSCs) constitute an endogenous reservoir for neurons that could potentially be harnessed for regenerative therapies in disease contexts such as neurodegeneration. However, in Alzheimer's disease (AD), NSCs lose plasticity and thus possible regenerative capacity. We investigate how NSCs lose their plasticity in AD by using starPEG-heparin-based hydrogels to establish a reductionist 3D cell-instructive neuro-microenvironment that promotes the proliferative and neurogenic ability of primary and induced human NSCs. We find that administration of AD-associated Amyloid-β42 causes classical neuropathology and hampers NSC plasticity by inducing kynurenic acid (KYNA) production. Interleukin-4 restores NSC proliferative and neurogenic ability by suppressing the KYNA-producing enzyme Kynurenine aminotransferase (KAT2), which is upregulated in APP/PS1dE9 mouse model of AD and in postmortem human AD brains. Thus, our culture system enables a reductionist investigation of regulation of human NSC plasticity for the identification of potential therapeutic targets for intervention in AD.
神经干细胞（NSCs）构成了神经元的内源性储备库，这些神经元可能被用于神经退行性疾病等疾病情况下的再生治疗。然而，在阿尔茨海默病（AD）中，NSCs 失去了可塑性，因此可能失去了再生能力。我们通过使用星形聚乙二醇-肝素基水凝胶来研究 NSCs 在 AD 中如何失去其可塑性，建立一个简化的 3D 细胞指令性神经微环境，促进原代和诱导的人 NSCs 的增殖和神经发生能力。我们发现，AD 相关的淀粉样蛋白-β42 的给药会导致典型的神经病理学，并通过诱导犬尿氨酸（KYNA）的产生来阻碍 NSC 的可塑性。白细胞介素-4 通过抑制 KYNA 产生酶犬尿氨酸氨基转移酶（KAT2）来恢复 NSCs 的增殖和神经发生能力，该酶在 AD 的 APP/PS1dE9 小鼠模型和 AD 患者死后的大脑中上调。因此，我们的培养系统使我们能够对人类 NSC 可塑性的调节进行简化研究，以确定 AD 干预的潜在治疗靶点。
