APP lysine 612 lactylation ameliorates amyloid pathology and memory decline in Alzheimer’s disease
Qiuyun Tian, Junjie Li, Bin Wu, Yayan Pang, Wenting He, Qian Xiao, Jiaojiao Wang, Lilin Yi, Na Tian, Xiuyu Shi, Lei Xia, Xin Tian, Mulan Chen, Yepeng Fan, Boqing Xu, Yuhan Tao, Weihong Song, Yehong Du, Zhifang Dong
Qiuyun Tian, Junjie Li, Bin Wu, Yayan Pang, Wenting He, Qian Xiao, Jiaojiao Wang, Lilin Yi, Na Tian, Xiuyu Shi, Lei Xia, Xin Tian, Mulan Chen, Yepeng Fan, Boqing Xu, Yuhan Tao, Weihong Song, Yehong Du, Zhifang Dong
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Research Article Aging Neuroscience

APP lysine 612 lactylation ameliorates amyloid pathology and memory decline in Alzheimer’s disease

Abstract

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.

Authors

Qiuyun Tian, Junjie Li, Bin Wu, Yayan Pang, Wenting He, Qian Xiao, Jiaojiao Wang, Lilin Yi, Na Tian, Xiuyu Shi, Lei Xia, Xin Tian, Mulan Chen, Yepeng Fan, Boqing Xu, Yuhan Tao, Weihong Song, Yehong Du, Zhifang Dong

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Figure 2

APP-K612la reduced APP amyloidogenic processing in vitro

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APP-K612la reduced APP amyloidogenic processing in vitro (A) LC-MS/MS sp...
(A) LC-MS/MS spectra of the lactylated peptides of APP-K612. (B–D) Sequencing map of the APP lactylation/delactylation in K354 (B), K363 (C), and K612 (D) mimic lysine mutation site. Blue-shaded lines and red-shaded boxes represent lysine mutation sites. (E–G) The relative protein levels of APP (E and F) and CTF-β (E and G) were assessed by Western blot in APPKO cells transfected with APPswe695, APPK354Q, and APPK354T mutant plasmids (n = 4 in each group). (H–J) The relative protein levels of APP (H and I) and CTF-β (H and J) were assessed by Western blot in APPKO cells transfected with APPswe695, APPK363Q, and APPK363T mutant plasmids (n = 4 in each group). (K–Q) The relative protein levels of APP (K and L), CTF-β (K and M), sAPP-β (K and N), ADAM10 (K and O), BACE1 (K and P), and PS1 (K and Q) were assessed by Western blot in APPKO cells transfected with APPswe695, APPK612Q, and APPK612T mutant plasmids (n = 4–6 in each group). Data were presented as mean ± SEM, *P < 0.05, and ***P < 0.001. 1-way ANOVA, followed by Tukey’s multiple comparisons test (F, G, I, J, and L–Q).