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 4

APP-K612la ameliorated synaptic and memory impairments in vivo.

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APP-K612la ameliorated synaptic and memory impairments in vivo. (A and B...
(A and B) Hippocampal CA1 LTP recorded from mouse brain slices (A) and the bar graphs of the average percentage changes in the fEPSP slope 55–60 minutes after TBS delivery (B) (n = 7–11 slices from 3–4 mice in each group). (C) Average heatmap during memory retrieval in the Barnes maze test. (D) Average heatmap during memory retrieval in the Morris water maze test. (E) The latency to the escape hole during spatial learning in the Barnes maze paradigm (n = 9–11 in each group). (F and G) Correct number of finding the escape hole (F) and the latency to finding the escape hole (G) during memory retrieval in the Barnes maze test (n = 9–11 in each group). (H) The latency for finding the hidden island during spatial learning in the Morris water maze test (n = 16–18 in each group). (I and J) Number of entries to the island zone (I) and the time in the hidden platform quadrant zone during spatial learning (J) in the Morris water maze test (n = 16–18 in each group). 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, F, G, I, and J) or 2-way ANOVA (E and H).