Blocking microglial activation of reactive astrocytes is neuroprotective in models of Alzheimer's disease.
Blocking microglial activation of reactive astrocytes is neuroprotective in models of Alzheimer's disease.
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DOI：
10.1186/s40478-021-01180-z
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发表时间：
2021-04-26
影响因子：
7.1
通讯作者：
Lee S
中科院分区：
文献类型：
--
作者：
Park JS;Kam TI;Lee S;Park H;Oh Y;Kwon SH;Song JJ;Kim D;Kim H;Jhaldiyal A;Na DH;Lee KC;Park EJ;Pomper MG;Pletnikova O;Troncoso JC;Ko HS;Dawson VL;Dawson TM;Lee S
阿尔茨海默病（AD）是年龄相关性痴呆的最常见原因。越来越多的证据表明，由小胶质细胞和星形胶质细胞介导的神经炎症有助于AD和其他神经退行性疾病的疾病进展和严重程度。在AD进展期间，驻留的小胶质细胞经历促炎活化，导致将静息星形胶质细胞转化为反应性星形胶质细胞的能力增加。因此，小胶质细胞是AD的主要治疗靶点，阻断小胶质细胞-星形胶质细胞活化可以限制AD中的神经变性。在此，我们报告了NLY 01，一种工程化exedin-4，胰高血糖素样肽-1受体（GLP-1 R）激动剂，通过GLP-1 R激活选择性阻断β-淀粉样蛋白（Aβ）诱导的小胶质细胞激活，抑制反应性星形胶质细胞的形成，并保护AD模型中的神经元。在两种转基因AD小鼠模型（5xFAD和3xTg-AD）中，NLY 01的重复皮下给药阻断了小胶质细胞介导的反应性星形胶质细胞转化并保留了神经元活力，从而改善了空间学习和记忆。我们的研究表明，GLP-1通路在AD中小胶质细胞反应性星形胶质细胞相关神经炎症中起关键作用，NLY 01的作用主要通过直接作用于Aβ诱导的GLP-1 R+小胶质细胞介导，有助于抑制星形胶质细胞反应性。这些结果表明，靶向小胶质细胞中上调的GLP-1 R是治疗AD和其他神经退行性疾病的可行疗法。在线版本包含补充材料，可通过10.1186/s40478-021-01180-z获得。
Alzheimer’s disease (AD) is the most common cause of age-related dementia. Increasing evidence suggests that neuroinflammation mediated by microglia and astrocytes contributes to disease progression and severity in AD and other neurodegenerative disorders. During AD progression, resident microglia undergo proinflammatory activation, resulting in an increased capacity to convert resting astrocytes to reactive astrocytes. Therefore, microglia are a major therapeutic target for AD and blocking microglia-astrocyte activation could limit neurodegeneration in AD. Here we report that NLY01, an engineered exedin-4, glucagon-like peptide-1 receptor (GLP-1R) agonist, selectively blocks β-amyloid (Aβ)-induced activation of microglia through GLP-1R activation and inhibits the formation of reactive astrocytes as well as preserves neurons in AD models. In two transgenic AD mouse models (5xFAD and 3xTg-AD), repeated subcutaneous administration of NLY01 blocked microglia-mediated reactive astrocyte conversion and preserved neuronal viability, resulting in improved spatial learning and memory. Our study indicates that the GLP-1 pathway plays a critical role in microglia-reactive astrocyte associated neuroinflammation in AD and the effects of NLY01 are primarily mediated through a direct action on Aβ-induced GLP-1R+ microglia, contributing to the inhibition of astrocyte reactivity. These results show that targeting upregulated GLP-1R in microglia is a viable therapy for AD and other neurodegenerative disorders. The online version contains supplementary material available at 10.1186/s40478-021-01180-z.
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影响因子：
25
作者：
Habib, Naomi;McCabe, Cristin;Medina, Sedi;Varshavsky, Miriam;Kitsberg, Daniel;Dvir-Szternfeld, Raz;Green, Gilad;Dionne, Danielle;Nguyen, Lan;Marshall, Jamie L.;Chen, Fei;Zhang, Feng;Kaplan, Tommy;Regev, Aviv;Schwartz, Michal
通讯作者：
Schwartz, Michal
影响因子：
6
作者：
Desai, Maya K.;Mastrangelo, Michael A.;Bowers, William J.
通讯作者：
Bowers, William J.
影响因子：
14
作者：
通讯作者：
--
Lixisenatide 可减少阿尔茨海默病 APP/PS1/tau 小鼠模型中的淀粉样斑块、神经原纤维缠结和神经炎症
DOI：
10.1016/j.bbrc.2017.11.114
发表时间：
2018-01-01
影响因子：
3.1
作者：
Cai, Hong-Yan;Yang, Jun-Ting;Qi, Jin-Shun
通讯作者：
Qi, Jin-Shun
影响因子：
4.7
作者：
McClean, Paula L.;Hoelscher, Christian
通讯作者：
Hoelscher, Christian