Intranasal Transplantation of Human Neural Stem Cells Ameliorates Alzheimer's Disease-Like Pathology in a Mouse Model.
Intranasal Transplantation of Human Neural Stem Cells Ameliorates Alzheimer's Disease-Like Pathology in a Mouse Model.
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鼻内移植人类神经干细胞可改善小鼠模型中的阿尔茨海默氏病样病理
DOI：
10.3389/fnagi.2021.650103
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发表时间：
2021
影响因子：
4.8
通讯作者：
Ma QH
中科院分区：
文献类型：
--
作者：
Lu MH;Ji WL;Chen H;Sun YY;Zhao XY;Wang F;Shi Y;Hu YN;Liu BX;Wu JW;Xu DE;Zheng JW;Liu CF;Ma QH
阿尔茨海默病（Alzheimer's disease，AD）是一种以记忆障碍为特征的神经退行性疾病，目前尚无有效的治疗方法。干细胞移植在多种疾病的治疗中显示出巨大的潜力。然而，干细胞治疗在神经系统疾病中的应用，特别是具有长期病程的疾病，如AD，由于脑血屏障的存在而受到递送方法的限制。到目前为止，在临床前和临床研究中，干细胞治疗神经系统疾病最常用的递送方法是颅内注射和鞘内注射，这两种方法都是侵入性的。在本研究中，我们使用重复鼻内递送人神经干细胞（hNSCs）到APP/PS1转基因小鼠的脑中，以研究hNSCs对AD病理学的影响。结果表明，鼻内移植的hNSCs存活，并表现出广泛的迁移和较高的神经元分化，具有相对有限的胶质细胞分化。一部分鼻内移植的hNSCs分化为胆碱能神经元，其拯救APP/PS1小鼠中的胆碱能功能障碍。此外，hNSC的鼻内移植通过上调β-淀粉样蛋白降解酶、胰岛素降解酶和脑啡肽酶的表达来减弱β-淀粉样蛋白积累。此外，鼻内移植的hNSCs改善其他AD样病理，包括神经炎症，胆碱能功能障碍，细胞周和突触丢失，同时增强成年海马神经发生，最终挽救APP/PS1转基因小鼠的认知缺陷。因此，我们的研究结果强调，鼻内移植hNSCs通过多种机制有利于认知，并显示出鼻内给药干细胞作为AD的非侵入性治疗策略的巨大潜力。
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory impairments, which has no effective therapy. Stem cell transplantation shows great potential in the therapy of various disease. However, the application of stem cell therapy in neurological disorders, especially the ones with a long-term disease course such as AD, is limited by the delivery approach due to the presence of the brain blood barrier. So far, the most commonly used delivery approach in the therapy of neurological disorders with stem cells in preclinical and clinical studies are intracranial injection and intrathecal injection, both of which are invasive. In the present study, we use repetitive intranasal delivery of human neural stem cells (hNSCs) to the brains of APP/PS1 transgenic mice to investigate the effect of hNSCs on the pathology of AD. The results indicate that the intranasally transplanted hNSCs survive and exhibit extensive migration and higher neuronal differentiation, with a relatively limited glial differentiation. A proportion of intranasally transplanted hNSCs differentiate to cholinergic neurons, which rescue cholinergic dysfunction in APP/PS1 mice. In addition, intranasal transplantation of hNSCs attenuates β-amyloid accumulation by upregulating the expression of β-amyloid degrading enzymes, insulin-degrading enzymes, and neprilysin. Moreover, intranasal transplantation of hNSCs ameliorates other AD-like pathology including neuroinflammation, cholinergic dysfunction, and pericytic and synaptic loss, while enhancing adult hippocampal neurogenesis, eventually rescuing the cognitive deficits of APP/PS1 transgenic mice. Thus, our findings highlight that intranasal transplantation of hNSCs benefits cognition through multiple mechanisms, and exhibit the great potential of intranasal administration of stem cells as a non-invasive therapeutic strategy for AD.
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影响因子：
2.1
作者：
Bali P;Lahiri DK;Banik A;Nehru B;Anand A
通讯作者：
Anand A
影响因子：
4.6
作者：
McGinley LM;Kashlan ON;Bruno ES;Chen KS;Hayes JM;Kashlan SR;Raykin J;Johe K;Murphy GG;Feldman EL
通讯作者：
Feldman EL
影响因子：
7.5
作者：
Duncan T;Valenzuela M
通讯作者：
Valenzuela M
影响因子：
6.4
作者：
Miners, J. Scott;van Helmond, Zoe;Love, Seth
通讯作者：
Love, Seth
影响因子：
16.1
作者：
Banks, William A.
通讯作者：
Banks, William A.