NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice.
NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice.
复制标题
作者：
阿尔茨海默病（AD）是世界上最常见的痴呆症。淀粉样β肽（Aβ）的沉积通过激活小胶质细胞驱动脑神经炎症。事实上，小胶质细胞中NLRP 3炎性体的Aβ活化是IL-1β成熟和随后炎症事件的基础。然而，NLRP 3激活是否有助于体内AD仍然是未知的。在这里，我们证明了强烈增强的活性半胱天冬酶-1在人类MCI和AD大脑中的表达，这表明炎性小体在这种神经退行性疾病中的作用。携带与熟悉AD相关突变的NLRP 3 −/−或caspase-1−/−小鼠在很大程度上免受空间记忆丧失和其他AD相关后遗症的影响，并表现出脑caspase-1和IL-1β激活减少以及Aβ清除增强。此外，NLRP 3炎性小体缺陷使小胶质细胞偏向M2表型，并导致阿尔茨海默病APP/PS1模型中Aβ沉积减少。这些结果揭示了NLRP 3/ caspase-1轴在AD发病机制中的重要作用，并表明NLRP 3炎性小体抑制代表了AD的新的治疗干预。
Alzheimer´s Disease (AD) is the world’s most common dementing illness. Deposition of amyloid beta peptide (Aβ) drives cerebral neuroinflammation by activating microglia. Indeed, Aβ activation of the NLRP3 inflammasome in microglia is fundamental for IL-1β maturation and subsequent inflammatory events. However, it remains unknown whether NLRP3 activation contributes to AD in vivo. Here, we demonstrate strongly enhanced active caspase-1 expression in human MCI and AD brains suggesting a role for the inflammasome in this neurodegenerative disease. NLRP3−/− or caspase-1−/− mice carrying mutations associated with familiar AD were largely protected from loss of spatial memory and other AD-associated sequelae and demonstrated reduced brain caspase-1 and IL-1β activation as well as enhanced Aβ clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of Aβ in the APP/PS1 model of Alzheimer’s disease. These results reveal an important role for the NLRP3 / caspase-1 axis in AD pathogenesis, and suggest that NLRP3 inflammasome inhibition represents a novel therapeutic intervention for AD.
登录
查看更多内容
影响因子：
5.3
作者：
Hickman, Suzanne E.;Allison, Elizabeth K.;El Khoury, Joseph
通讯作者：
El Khoury, Joseph
影响因子：
4.7
作者：
Jaeger, Sebastian;Leuchtenberger, Stefanie;Pietrzik, Claus U.
通讯作者：
Pietrzik, Claus U.
影响因子：
25
作者：
Chapman, PF;White, GL;Hsiao, KK
通讯作者：
Hsiao, KK
影响因子：
3.3
作者：
Lee, C. Y. Daniel;Landreth, Gary E.
通讯作者：
Landreth, Gary E.
DOI：
10.1126/science.1209236
发表时间：
2011-11-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Ho VM;Lee JA;Martin KC
通讯作者：
Martin KC