Role of the caspase-8/RIPK3 axis in Alzheimer's disease pathogenesis and Aβ-induced NLRP3 inflammasome activation.
Role of the caspase-8/RIPK3 axis in Alzheimer's disease pathogenesis and Aβ-induced NLRP3 inflammasome activation.
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DOI：
10.1172/jci.insight.157433
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发表时间：
2023-02-08
期刊：
影响因子：
8
通讯作者：
Deppmann CD
中科院分区：
文献类型：
--
作者：
Kumar S;Budhathoki S;Oliveira CB;Kahle AD;Calhan OY;Lukens JR;Deppmann CD
阿尔茨海默病（AD）中细胞死亡和炎症的分子介质尚未完全阐明。半胱天冬酶 - 8是几种细胞死亡和炎症通路的关键调节因子；然而，其在AD发病机制中的作用尚未得到详细研究。在缺乏半胱天冬酶 - 8的情况下，小鼠由于受体相互作用蛋白激酶3依赖性（RIPK3依赖性）坏死性凋亡过度而在胚胎期死亡。RIPK3和半胱天冬酶 - 8复合突变体可挽救胚胎致死性，我们利用这一点在淀粉样β介导（Aβ介导）的AD小鼠模型中研究了这些通路的作用。我们发现半胱天冬酶 - 8和RIPK3的联合缺失，而不是单独的RIPK3缺失，导致携带人早老素1和具有5个家族性AD突变的淀粉样前体蛋白（5xFAD）的AD小鼠模型中Aβ沉积和小胶质细胞增生减少。尽管半胱天冬酶 - 8在细胞死亡中的作用众所周知，但它似乎并不影响5xFAD模型中的细胞丢失。相反，我们发现半胱天冬酶 - 8是Aβ驱动的炎性体基因表达和白细胞介素 - 1β释放的关键调节因子。有趣的是，RIPK3的缺失对疾病进展只有适度的影响，这表明在Aβ淀粉样变性的中期，抑制坏死性凋亡或RIPK3介导的细胞因子通路并不关键。这些发现表明，针对半胱天冬酶 - 8的治疗方法可能是限制AD中Aβ淀粉样变性和神经炎症的一种新策略。
The molecular mediators of cell death and inflammation in Alzheimer’s disease (AD) have yet to be fully elucidated. Caspase-8 is a critical regulator of several cell death and inflammatory pathways; however, its role in AD pathogenesis has not yet been examined in detail. In the absence of caspase-8, mice are embryonic lethal due to excessive receptor interacting protein kinase 3–dependent (RIPK3-dependent) necroptosis. Compound RIPK3 and caspase-8 mutants rescue embryonic lethality, which we leveraged to examine the roles of these pathways in an amyloid β–mediated (Aβ-mediated) mouse model of AD. We found that combined deletion of caspase-8 and RIPK3, but not RIPK3 alone, led to diminished Aβ deposition and microgliosis in the mouse model of AD carrying human presenilin 1 and amyloid precursor protein with 5 familial AD mutations (5xFAD). Despite its well-known role in cell death, caspase-8 did not appear to affect cell loss in the 5xFAD model. In contrast, we found that caspase-8 was a critical regulator of Aβ-driven inflammasome gene expression and IL-1β release. Interestingly, loss of RIPK3 had only a modest effect on disease progression, suggesting that inhibition of necroptosis or RIPK3-mediated cytokine pathways is not critical during midstages of Aβ amyloidosis. These findings suggest that therapeutics targeting caspase-8 may represent a novel strategy to limit Aβ amyloidosis and neuroinflammation in AD.
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