ArticleThe Journal of clinical investigation2025
APP lysine 612 lactylation ameliorates amyloid pathology and memory decline in Alzheimer's disease.
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Article in The Journal of clinical investigation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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32 citing papers in PubMed.
- Bisphenol A Exposure Perturbs the Immune Microenvironment in Alzheimer's Disease: Insights from Network Toxicology and Single-Cell Transcriptomics.Journal of molecular neuroscience : MN · 2026Article
- Roles of lactate and protein lactylation in neurogenesis and neurodegenerative disease.Journal of translational medicine · 2026Review
- H3K18 Lactylation Promotes Cell Proliferation in T-Cell Acute Lymphoblastic Leukemia.Journal of cellular biochemistry · 2026Article
- Novel protein acylations in Alzheimer's disease: Molecular, mechanisms, biological significance, and diagnostic and therapeutic potentials.Journal of advanced research · 2026Review
- Neuroinflammation in Alzheimer's and Parkinson's diseases: pathogenic mechanisms and therapeutic strategies.Translational neurodegeneration · 2026Review
- Protein lactylation in health and diseases: molecular mechanisms, biological significance, and clinical implications.Signal transduction and targeted therapy · 2026Review
- Hyperglycemia impairs cognitive function by inducing mitochondrial damage through lactylation of LRPPRC at K223.EMBO molecular medicine · 2026Article
- SHMT2 deficiency disrupts transcriptional regulation through homocysteine-mediated suppression of histone lactylation in Huntington's disease models.The Journal of clinical investigation · 2026Article
- Genome-Wide CRISPR Screening Identifies Genetic Modulators of Amyloid Precursor Protein Processing.International journal of molecular sciences · 2026Article
- Lactate metabolism links reactive microglia, amyloid pathology, and Aβ dynamics.Journal of neuroinflammation · 2026Article
- Comparative analyses of regional and temporal transcriptomics of early human and mouse central nervous systems.iScience · 2026Article
- Alzheimer's disease: from molecular pathways to therapies.Molecular biomedicine · 2026Review
- Lactylation and acetylation: parallel paths, divergent deeds, and research dilemmas.Journal of translational medicine · 2026Review
- Global profiling of protein lactylation in pancreatic ductal adenocarcinoma.Scientific reports · 2026Article
- E2F1-mediated 53BP2 lactylation stabilizes p53 to induce cochlear hair cell apoptosis in mouse age-related hearing loss.Clinical epigenetics · 2026Article
- Dynamic regulation of TBK1 lactylation shapes antiviral immune responses.Cellular & molecular immunology · 2026Article
- The Lactate Nexus: A Molecular Bridge Linking Physical Activity, Sleep, and Cognitive Enhancement.Biomedicines · 2026Review
- PTM encoding: decoding the mechanisms of exercise-induced metabolic memory through spatiotemporal modification networks.Frontiers in sports and active living · 2026Review
- Pyruvate kinase M2 in Alzheimer's disease: from dysregulation to therapeutic inhibition.Brain communications · 2026Review
- Traditional Chinese Medicine and Ferroptosis in Alzheimer's Disease: A Potential Therapeutic Approach.Drug design, development and therapy · 2026Review
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Authors and funding
19 authors.
Qiuyun TianGrowth, 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.
Junjie LiGrowth, 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.
Bin WuGrowth, 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.
Yayan PangGrowth, 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.
Wenting HeGrowth, 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.
Qian XiaoGrowth, 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.
Jiaojiao WangGrowth, 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.
Lilin YiGrowth, 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.
Na TianGrowth, 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.
Xiuyu ShiGrowth, 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.
Lei XiaGrowth, 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.
Xin TianDepartment of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
Mulan ChenGrowth, 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.
Yepeng FanGrowth, 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.
Boqing XuGrowth, 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.
Yuhan TaoGrowth, 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.
Weihong SongGrowth, 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.
Yehong DuGrowth, 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.
Zhifang DongGrowth, 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.
Funding
No grant is acknowledged in the PubMed record.
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.
Indexed as
Alzheimer DiseaseAmyloid beta-Protein PrecursorMice, TransgenicAmino Acid SubstitutionAmyloid beta-PeptidesAmyloid Precursor Protein SecretasesAnimalsAspartic Acid EndopeptidasesDisease Models, AnimalHumansLysineMaleMemory DisordersMiceMutation, MissenseProtein Processing, Post-TranslationalAmyloid beta-PeptidesAmyloid beta-Protein PrecursorAmyloid Precursor Protein SecretasesAPP protein, humanAspartic Acid EndopeptidasesLysineAgingAlzheimer diseaseNeurodegenerationNeuroscience
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.