Department of Pharmacology, Basic Medicine College, Key Laboratory of Anti-Inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei, 230032, China.
Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, Anhui, China.
Behav Brain Funct. 2023 Apr 13;19(1):7. doi: 10.1186/s12993-023-00209-8.
Increasing evidence has shown that the NOD-like receptor protein 1 (NLRP1) inflammasome is associated with Aβ generation and deposition, which contributes to neuronal damage and neuronal-inflammation in Alzheimer's disease (AD). However, the specific mechanism of NLRP1 inflammasome in the pathogenesis of AD is still unclear. It has been reported that autophagy dysfunction can aggravate the pathological symptoms of AD and plays an important role in regulating Aβ generation and clearance. We hypothesized that NLRP1 inflammasome activation may induce autophagy dysfunction contributing to the progression of AD. In the present study, we observed the relationship between Aβ generation and NLRP1 inflammasome activation, as well as AMPK/mTOR mediated-autophagy dysfunction in WT 9-month-old (M) mice, APP/PS1 6 M and APP/PS1 9 M mice. Additionally, we further studied the effect of NLRP1 knockdown on cognitive function, Aβ generation, neuroinflammation and AMPK/mTOR mediated autophagy in APP/PS1 9 M mice. Our results indicated that NLRP1 inflammasome activation and AMPK/mTOR mediated-autophagy dysfunction are closely implicated in Aβ generation and deposition in APP/PS1 9 M mice, but not in APP/PS1 6 M mice. Meanwhile, we found that knockdown of NLRP1 significantly improved learning and memory impairments, decreased the expressions of NLRP1, ASC, caspase-1, p-NF-κB, IL-1β, APP, CTF-β, BACE1 and Aβ, and decreased the level of p-AMPK, Beclin 1 and LC3 II, and increased the level of p-mTOR and P62 in APP/PS1 9 M mice. Our study suggested that inhibition of NLRP1 inflammasome activation improves AMPK/mTOR mediated-autophagy dysfunction, resulting in the decrease of Aβ generation, and NLRP1 and autophagy might be important targets to delay the progression of AD.
越来越多的证据表明，NOD 样受体蛋白 1（NLRP1）炎症小体与 Aβ 的产生和沉积有关，这有助于阿尔茨海默病（AD）中的神经元损伤和神经炎症。然而，NLRP1 炎症小体在 AD 发病机制中的具体机制尚不清楚。据报道，自噬功能障碍可加重 AD 的病理症状，并在调节 Aβ 的产生和清除中发挥重要作用。我们假设 NLRP1 炎症小体的激活可能导致自噬功能障碍，从而促进 AD 的进展。在本研究中，我们观察了 WT9 月龄（M）小鼠、APP/PS16M 和 APP/PS19M 小鼠中 Aβ 的产生与 NLRP1 炎症小体激活以及 AMPK/mTOR 介导的自噬功能障碍之间的关系。此外，我们进一步研究了 NLRP1 敲低对 APP/PS19M 小鼠认知功能、Aβ 的产生、神经炎症和 AMPK/mTOR 介导的自噬的影响。我们的结果表明，NLRP1 炎症小体的激活和 AMPK/mTOR 介导的自噬功能障碍与 APP/PS19M 小鼠中 Aβ 的产生和沉积密切相关，但与 APP/PS16M 小鼠无关。同时，我们发现，敲低 NLRP1 可显著改善学习和记忆障碍，降低 NLRP1、ASC、caspase-1、p-NF-κB、IL-1β、APP、CTF-β、BACE1 和 Aβ 的表达，增加 p-AMPK、Beclin1 和 LC3 II 的水平，并降低 APP/PS19M 小鼠中 p-mTOR 和 P62 的水平。我们的研究表明，抑制 NLRP1 炎症小体的激活可改善 AMPK/mTOR 介导的自噬功能障碍，从而减少 Aβ 的产生，NLRP1 和自噬可能是延缓 AD 进展的重要靶点。
