Halle Annett, Hornung Veit, Petzold Gabor C, Stewart Cameron R, Monks Brian G, Reinheckel Thomas, Fitzgerald Katherine A, Latz Eicke, Moore Kathryn J, Golenbock Douglas T
Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Nat Immunol. 2008 Aug;9(8):857-65. doi: 10.1038/ni.1636. Epub 2008 Jul 11.
The fibrillar peptide amyloid-beta (A beta) has a chief function in the pathogenesis of Alzheimer's disease. Interleukin 1 beta (IL-1 beta) is a key cytokine in the inflammatory response to A beta. Insoluble materials such as crystals activate the inflammasome formed by the cytoplasmic receptor NALP3, which results in the release of IL-1 beta. Here we identify the NALP3 inflammasome as a sensor of A beta in a process involving the phagocytosis of A beta and subsequent lysosomal damage and release of cathepsin B. Furthermore, the IL-1 beta pathway was essential for the microglial synthesis of proinflammatory and neurotoxic factors, and the inflammasome, caspase-1 and IL-1 beta were critical for the recruitment of microglia to exogenous A beta in the brain. Our findings suggest that activation of the NALP3 inflammasome is important for inflammation and tissue damage in Alzheimer's disease.
纤维状肽β淀粉样蛋白（Aβ）在阿尔茨海默病的发病机制中起主要作用。白细胞介素1β（IL-1β）是对Aβ炎症反应中的关键细胞因子。诸如晶体之类的不溶性物质激活由细胞质受体NALP3形成的炎性小体，这导致IL-1β的释放。在这里，我们确定NALP3炎性小体是Aβ的一种传感器，该过程涉及Aβ的吞噬作用以及随后的溶酶体损伤和组织蛋白酶B的释放。此外，IL-1β途径对于小胶质细胞合成促炎和神经毒性因子至关重要，并且炎性小体、半胱天冬酶-1和IL-1β对于小胶质细胞向脑中外源性Aβ的募集至关重要。我们的研究结果表明，NALP3炎性小体的激活对于阿尔茨海默病中的炎症和组织损伤很重要。
