AAV serotype 2/1-mediated gene delivery of anti-inflammatory interleukin-10 enhances neurogenesis and cognitive function in APP+PS1 mice.
AAV serotype 2/1-mediated gene delivery of anti-inflammatory interleukin-10 enhances neurogenesis and cognitive function in APP+PS1 mice.
复制标题
AAV血清型2/1介导的抗炎白细胞介素-10的基因递送增强了APP+PS1小鼠的神经发生和认知功能。
作者：
脑炎症是一把双刃剑：它是大脑修复急性损伤所必需的，而慢性炎症和自身免疫性疾病则是神经致病性的。某些促炎细胞因子和趋化因子与认知功能障碍和神经变性密切相关。代表性的抗炎细胞因子，如白细胞介素(IL)-10，可以抑制神经炎症，并在改善神经退行性疾病，如阿尔茨海默病（AD）方面具有重要的治疗潜力。在这里，我们发现腺相关病毒（AAV）血清型2/1杂交介导的小鼠IL-10基因的神经元表达改善了APP+PS1双基因小鼠的认知功能障碍。AAV2/1感染海马神经元导致IL-10持续表达而不渗漏到血液中，减少星状/小胶质细胞增生，提高血浆淀粉样蛋白-β肽（Aβ）水平，增强神经发生。此外，IL-10水平的提高改善了空间学习，这是由径向臂水迷宫确定的。最后，IL-10刺激的小胶质细胞增强了共培养系统中原代神经干细胞的增殖，但没有促进其分化，而IL-10本身没有影响。我们的数据表明，IL-10基因传递具有非a β靶向治疗AD的治疗潜力。
Brain inflammation is a double-edged sword: it is required for brain repair in acute damage, whereas chronic inflammation and autoimmune disorders are neuropathogenic. Certain pro-inflammatory cytokines and chemokines are closely related to cognitive dysfunction and neurodegeneration. Representative anti-inflammatory cytokines, such as interleukin (IL)-10, can suppress neuroinflammation and have significant therapeutic potentials in ameliorating neurodegenerative disorders, such as Alzheimer’s disease (AD). Here, we show that adeno-associated virus (AAV) serotype 2/1 hybrid-mediated neuronal expression of the mouse IL-10 gene ameliorates cognitive dysfunction in APP+PS1 bigenic mice. AAV2/1 infection of hippocampal neurons resulted in sustained expression of IL-10 without its leakage into the blood, reduced astro/microgliosis, enhanced plasma amyloid-β peptide (Aβ) levels, and enhanced neurogenesis. Moreover, increased levels of IL-10 improved spatial learning as determined by the radial arm water maze. Finally, IL-10-stimulated microglia enhanced proliferation but not differentiation of primary neural stem cells in the co-culture system, while IL-10 itself had no effect. Our data suggest that IL-10 gene delivery has a therapeutic potential for a non-Aβ-targeted treatment of AD.
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DOI：
10.1038/mt.2009.44
发表时间：
2009-05
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
通讯作者：
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影响因子：
11.2
作者：
Frenkel, Dan;Puckett, Lindsay;Weiner, Howard L.
通讯作者：
Weiner, Howard L.
影响因子：
82.9
作者：
Holcomb, L;Gordon, MN;Duff, K
通讯作者：
Duff, K
影响因子：
4.2
作者：
Arimoto, Toyoko;Choi, Dong-Young;Bing, Guoying
通讯作者：
Bing, Guoying
影响因子：
5.3
作者：
Dietrich, WD;Busto, R;Bethea, JR
通讯作者：
Bethea, JR