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 7

APP-K612la promoted the endosomal-lysosomal degradation process via CD2AP.

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APP-K612la promoted the endosomal-lysosomal degradation process via CD2A...
(A and B) The relative protein levels of APP treated with chloroquine (CQ, 50 nM) for 24 hours were assessed by Western blot in APPKO cells transfected with APPswe695, APPK612Q, and APPK612T mutant plasmids (n = 4 in each group). (C) Schematic representation of APP degradation assay using surface protein biotinylation. (D) Degradation of surface biotinylated APP (Biotin-APP, 0 minutes) chased for 60 minutes and 120 minutes in cells (n = 5 in each group). (E–G) The relative protein levels of CTF-β (E), sAPP-β (F), and PS1 (G) in endosomes were assessed by Western blot (n = 3–5 in each group). (H) Interactions among APPswe695, APPK612Q, and APPK612T group APP and BACE1 proteins were detected by coimmunoprecipitation in endosomal protein lysates (n = 3 per group). (I) The relative protein levels of CD2AP were assessed by Western blot in cells (n = 4 in each group). (J) The relative protein levels of CD2AP in endosomes were assessed by Western blot in cells (n = 4 in each group). (K) Overexpression of CD2AP plasmid cotransfected with APPswe695, APPK612Q, and APPK612T mutant plasmids in APPKO cells, and the relative protein levels of APP in endosomes were assessed by Western blotting (n = 4 per group). (L) Interactions among APPswe695, APPK612Q, and APPK612T group APP and CD2AP proteins were detected by coimmunoprecipitation in endosomal protein lysates (n = 3 per group). (M and N) Representative confocal fluorescence images of APP costained with CD2AP in APPswe695, APPK612Q, and APPK612T groups (M), as well as the colocalization of APP with CD2AP in multiple confocal images quantified by calculating the Manders’ overlap coefficient (N) (n > 30 cells in each group; scale bar: 5 μm.). Data were presented as mean ± SEM, *P < 0.05, **P < 0.01, ***P < 0.001. 1-way ANOVA, followed by Tukey’s multiple comparisons test (B, E–G, I–K, and N) or 2-way ANOVA (D).