Cheng Kuan, Wang Jingjing, Chen Qingxing, Zhao Gang, Pang Yang, Xu Ye, Ge Junbo, Zhu Wenqing
Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China.
Department of Emergency, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China.
Ann Transl Med. 2021 Oct;9(20):1560. doi: 10.21037/atm-21-4931.
Myocardial infarction (MI) has been suggested as a critical predisposing factor for Alzheimer's disease (AD); however, the underlying mechanisms remain unknown. PYD domains-containing protein 3 (NLRP3) is a key factor to mediate inflammasome formation. Previous studies have shown that NLRP3 activation in brain microglia is required for AD; however, its possible role in MI-induced future development of neurodegeneration is not yet understood. These questions were addressed in the current study.
We generated microglia-specific NLRP3 mutation mice in the AD-prone APP/PS1 background (APP/PS1/NLRP3), and studied the neurodegeneration in these mice after MI compared to the control wild-type C57/BL6J or APP/PS1 mice. NLRP3, IL-1β and caspase-1 levels were determined by Enzyme-linked immunoassay (ELISA). The heart function was determined by the slope of end systolic pressure-volume relationship, left ventricular end diastolic pressure, the positive maximal pressure derivative as well as the degree of fibrosis by Masson's trichrome staining. Mouse behavior measurement includes Morris water-maze test and motor assessment.
We found that compared with the control wild-type C57/BL6J or APP/PS1 mice, the effects of MI on the subsequent development of defected spatial reference memory and motor activity were all attenuated in APP/PS1/NLRP3 mice, likely resulting from the reduced formation of amyloid-beta peptide aggregates (Aβ) plaques.
NLRP3 may play a non-redundant role in the MI-induced future development of AD.
心肌梗死（MI）被认为是阿尔茨海默病（AD）的一个关键诱发因素；然而，其潜在机制仍不清楚。含PYD结构域的蛋白3（NLRP3）是介导炎性小体形成的关键因素。先前的研究表明，脑小胶质细胞中的NLRP3激活是AD所必需的；然而，其在MI诱导的未来神经退行性变发展中的可能作用尚不清楚。本研究解决了这些问题。
我们在易患AD的APP/PS1背景下生成了小胶质细胞特异性NLRP3突变小鼠（APP/PS1/NLRP3），并与对照野生型C57/BL6J或APP/PS1小鼠相比，研究了MI后这些小鼠的神经退行性变。通过酶联免疫吸附测定（ELISA）测定NLRP3、白细胞介素-1β和半胱天冬酶-1水平。通过收缩末期压力-容积关系斜率、左心室舒张末期压力、最大正向压力导数以及用Masson三色染色法测定纤维化程度来确定心脏功能。小鼠行为测量包括莫里斯水迷宫试验和运动评估。
我们发现，与对照野生型C57/BL6J或APP/PS1小鼠相比，MI对APP/PS1/NLRP小鼠后续出现的空间参考记忆缺陷和运动活动的影响均减弱，这可能是由于淀粉样β肽聚集体（Aβ）斑块形成减少所致。
NLRP3可能在MI诱导的AD未来发展中起非冗余作用。
