Tian Qiuyun, Li Junjie, Wu Bin, Pang Yayan, He Wenting, Xiao Qian, Wang Jiaojiao, Yi Lilin, Tian Na, Shi Xiuyu, Xia Lei, Tian Xin, Chen Mulan, Fan Yepeng, Xu Boqing, Tao Yuhan, Song Weihong, Du Yehong, Dong Zhifang
Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
J Clin Invest. 2025 Jan 2;135(1):e184656. doi: 10.1172/JCI184656.
Posttranslational modification (PTM) of the amyloid precursor protein (APP) plays a critical role in Alzheimer's disease (AD). Recent evidence reveals that lactylation modification, as a novel PTM, is implicated in the occurrence and development of AD. However, whether and how APP lactylation contributes to both the pathogenesis and cognitive function in AD remains unknown. Here, we observed a reduction in APP lactylation in AD patients and AD model mice and cells. Proteomic mass spectrometry analysis further identified lysine 612 (APP-K612la) as a crucial site for APP lactylation, influencing APP amyloidogenic processing. A lactyl-mimicking mutant (APPK612T) reduced amyloid-β peptide (Aβ) generation and slowed down cognitive deficits in vivo. Mechanistically, APPK612T appeared to facilitate APP trafficking and metabolism. However, lactylated APP entering the endosome inhibited its binding to BACE1, suppressing subsequent cleavage. Instead, it promoted protein interaction between APP and CD2-associated protein (CD2AP), thereby accelerating the endosomal-lysosomal degradation pathway of APP. In the APP23/PS45 double-transgenic mouse model of AD, APP-Kla was susceptible to L-lactate regulation, which reduced Aβ pathology and repaired spatial learning and memory deficits. Thus, these findings suggest that targeting APP lactylation may be a promising therapeutic strategy for AD in humans.
淀粉样前体蛋白（APP）的翻译后修饰（PTM）在阿尔茨海默病（AD）中起着关键作用。最近的证据表明，乳酸化修饰作为一种新的PTM，与AD的发生和发展有关。然而，APP乳酸化是否以及如何影响AD的发病机制和认知功能仍不清楚。在这里，我们观察到AD患者、AD模型小鼠和细胞中APP乳酸化水平降低。蛋白质组质谱分析进一步确定赖氨酸612（APP-K612la）是APP乳酸化的关键位点，影响APP的淀粉样生成过程。一种模拟乳酸化的突变体（APPK612T）在体内减少了淀粉样β肽（Aβ）的生成并减缓了认知缺陷。机制上，APPK612T似乎促进了APP的运输和代谢。然而，进入内体的乳酸化APP抑制了其与β-分泌酶1（BACE1）的结合，抑制了随后的切割。相反，它促进了APP与CD2相关蛋白（CD2AP）之间的蛋白质相互作用，从而加速了APP的内体-溶酶体降解途径。在AD的APP23/PS45双转基因小鼠模型中，APP-Kla易受L-乳酸的调节，这减少了Aβ病理并修复了空间学习和记忆缺陷。因此，这些发现表明，针对APP乳酸化可能是一种有前景的人类AD治疗策略。
