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Research ArticleAgingNeuroscience
Open Access | 
10.1172/JCI184656
1Growth, 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.
2Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
3Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, China.
4Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada.
5Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Zhejiang Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Address correspondence to: Yehong Du or Zhifang Dong, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China. zfdong@cqmu.edu.cn (ZD) dudu0000807@126.com (YD).
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1Growth, 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.
2Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
3Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, China.
4Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada.
5Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Zhejiang Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Address correspondence to: Yehong Du or Zhifang Dong, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China. zfdong@cqmu.edu.cn (ZD) dudu0000807@126.com (YD).
Find articles by Li, J. in: JCI | PubMed | Google Scholar
1Growth, 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.
2Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
3Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, China.
4Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada.
5Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Zhejiang Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Address correspondence to: Yehong Du or Zhifang Dong, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China. zfdong@cqmu.edu.cn (ZD) dudu0000807@126.com (YD).
Find articles by Wu, B. in: JCI | PubMed | Google Scholar
1Growth, 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.
2Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
3Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, China.
4Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada.
5Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Zhejiang Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Address correspondence to: Yehong Du or Zhifang Dong, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China. zfdong@cqmu.edu.cn (ZD) dudu0000807@126.com (YD).
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1Growth, 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.
2Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
3Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, China.
4Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada.
5Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Zhejiang Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Address correspondence to: Yehong Du or Zhifang Dong, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China. zfdong@cqmu.edu.cn (ZD) dudu0000807@126.com (YD).
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1Growth, 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.
2Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
3Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, China.
4Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada.
5Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Zhejiang Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Address correspondence to: Yehong Du or Zhifang Dong, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China. zfdong@cqmu.edu.cn (ZD) dudu0000807@126.com (YD).
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1Growth, 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.
2Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
3Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, China.
4Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada.
5Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Zhejiang Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Address correspondence to: Yehong Du or Zhifang Dong, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China. zfdong@cqmu.edu.cn (ZD) dudu0000807@126.com (YD).
Find articles by Wang, J. in: JCI | PubMed | Google Scholar
1Growth, 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.
2Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
3Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, China.
4Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada.
5Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Zhejiang Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Address correspondence to: Yehong Du or Zhifang Dong, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China. zfdong@cqmu.edu.cn (ZD) dudu0000807@126.com (YD).
Find articles by Yi, L. in: JCI | PubMed | Google Scholar
1Growth, 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.
2Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
3Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, China.
4Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada.
5Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Zhejiang Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Address correspondence to: Yehong Du or Zhifang Dong, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China. zfdong@cqmu.edu.cn (ZD) dudu0000807@126.com (YD).
Find articles by Tian, N. in: JCI | PubMed | Google Scholar
1Growth, 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.
2Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
3Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, China.
4Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada.
5Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Zhejiang Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Address correspondence to: Yehong Du or Zhifang Dong, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China. zfdong@cqmu.edu.cn (ZD) dudu0000807@126.com (YD).
Find articles by Shi, X. in: JCI | PubMed | Google Scholar
1Growth, 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.
2Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
3Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, China.
4Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada.
5Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Zhejiang Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Address correspondence to: Yehong Du or Zhifang Dong, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China. zfdong@cqmu.edu.cn (ZD) dudu0000807@126.com (YD).
Find articles by Xia, L. in: JCI | PubMed | Google Scholar
1Growth, 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.
2Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
3Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, China.
4Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada.
5Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Zhejiang Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Address correspondence to: Yehong Du or Zhifang Dong, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China. zfdong@cqmu.edu.cn (ZD) dudu0000807@126.com (YD).
Find articles by Tian, X. in: JCI | PubMed | Google Scholar
1Growth, 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.
2Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
3Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, China.
4Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada.
5Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Zhejiang Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Address correspondence to: Yehong Du or Zhifang Dong, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China. zfdong@cqmu.edu.cn (ZD) dudu0000807@126.com (YD).
Find articles by Chen, M. in: JCI | PubMed | Google Scholar
1Growth, 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.
2Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
3Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, China.
4Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada.
5Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Zhejiang Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Address correspondence to: Yehong Du or Zhifang Dong, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China. zfdong@cqmu.edu.cn (ZD) dudu0000807@126.com (YD).
Find articles by Fan, Y. in: JCI | PubMed | Google Scholar
1Growth, 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.
2Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
3Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, China.
4Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada.
5Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Zhejiang Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Address correspondence to: Yehong Du or Zhifang Dong, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China. zfdong@cqmu.edu.cn (ZD) dudu0000807@126.com (YD).
Find articles by Xu, B. in: JCI | PubMed | Google Scholar
1Growth, 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.
2Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
3Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, China.
4Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada.
5Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Zhejiang Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Address correspondence to: Yehong Du or Zhifang Dong, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China. zfdong@cqmu.edu.cn (ZD) dudu0000807@126.com (YD).
Find articles by Tao, Y. in: JCI | PubMed | Google Scholar
1Growth, 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.
2Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
3Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, China.
4Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada.
5Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Zhejiang Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Address correspondence to: Yehong Du or Zhifang Dong, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China. zfdong@cqmu.edu.cn (ZD) dudu0000807@126.com (YD).
Find articles by Song, W. in: JCI | PubMed | Google Scholar
1Growth, 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.
2Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
3Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, China.
4Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada.
5Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Zhejiang Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Address correspondence to: Yehong Du or Zhifang Dong, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China. zfdong@cqmu.edu.cn (ZD) dudu0000807@126.com (YD).
Find articles by Du, Y. in: JCI | PubMed | Google Scholar
1Growth, 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.
2Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
3Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education), Chongqing Medical University, Chongqing, China.
4Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada.
5Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer’s Disease of Zhejiang Province, Zhejiang Clinical Research Center for Mental Disorders, School of Mental Health and The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Address correspondence to: Yehong Du or Zhifang Dong, Children’s Hospital of Chongqing Medical University, Chongqing 400014, China. zfdong@cqmu.edu.cn (ZD) dudu0000807@126.com (YD).
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Published January 2, 2025 - More info
Published in Volume 135, Issue 1 on January 2, 2025
AbstractPosttranslational 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.
Graphical Abstract
Introduction
Alzheimer’s disease (AD) stands as one of the most common progressive degenerative diseases of the central nervous system, and its pathogenesis is extremely complex and not fully elucidated. Pathological deposition of amyloid-β (Aβ) peptides is a pivotal pathological hallmark of AD, believed to be a primary driver of subsequent neuronal loss and eventual cognitive decline in AD (1–3). Aβ originates from sequential proteolytic cleavages of the Aβ precursor protein (APP) by β-secretase (BACE1) and γ-secretase, with a major component being presenilin-1 (PS1) (4, 5). A growing body of evidence suggests that protein posttranslational modification (PTM) serves as an effective and rapid regulatory mechanism linking metabolism to protein and cellular function (6), playing a critical role in the pathology of neurological disorders (7, 8). In recent years, more and more studies have revealed that abnormal APP PTM could serve as a key factor affecting APP metabolism and Aβ deposition by regulating processes such as APP hydrolysis and transportation (9–11). APP undergoes various forms of PTMs, including phosphorylation (12, 13), ubiquitination (14, 15), glycosylation (16–18), palmitoylation (19–21), succinylation (22), acetylation (11), and small ubiquitin–related modifier (SUMO) (23, 24). These modifications actively participate in and regulate the pathological processes of AD. Therefore, investigating new PTMs and their associated regulatory mechanisms in APP holds the potential to identify drug targets for the treatment of AD.
Lactate was initially considered as a metabolic byproduct and a potential energy substrate, supporting up to 10% of brain energy metabolism (25). However, recent studies have revealed that lactate can also exert its biological activity through a protein PTM, referred to as lactylation modification (26–29). In 2019, Zhang and colleagues first reported that lactate accumulating during metabolism can serve as a precursor for stimulating histone lactylation at lysine residues (Kla), thereby turning on gene expression to promote homeostasis (26). Subsequent studies have demonstrated that Kla modification is implicated in various cellular functions related to glycolysis (19), macrophage polarization (30, 31), modulation of inflammation (32), and tumor-related diseases (33–35). In addition, Kla has also been reported to have a unique function in the regulation of brain function and the development of brain diseases (35–37). For example, histone H1 Kla occurs in brain cells, and its levels can be regulated by neuronal excitation and social defeat stress (36). During cerebral ischemia, Kla of key proteins in the Ca2+ signaling pathway, including Scl25a4, Slc25a5, and Vdac1, may influence mitochondrial function and neuronal injury (38). Levels of both Pan-Kla and H4K12la are increased in the prefrontal cortex and hippocampus of 5×FAD model mice, where H4K12La is enriched in the promoter of glycolytic genes and promotes transcription of glycolytic genes (29). However, it remains unclear whether APP, a key gene implicated in AD pathogenesis, undergoes Kla modification (APP-Kla) and how it contributes to the development of AD.
In this study, we identified that the decrease in K612 lactylation is a critical pathological change leading to APP amyloidogenic processing in AD brains using mass spectroscopy and a lactyl-mimicking mutant (APPK612T). Furthermore, we observed that APPK612T promoted APP endosomal-lysosomal degradation by enhancing the interaction between APP and CD2AP in cellular endosomes. Finally, our findings indicated that APP-Kla was susceptible to modulation by L-lactate, which decreased Aβ burden and improved spatial learning and memory in the AD model of APP23/PS45 double-transgenic mice. Our study thus suggests that promoting APP-Kla may represent a promising therapeutic strategy for treating AD.
ResultsReduced expression level of APP lactylation modification in AD. We first detected the protein expression levels of pan-lysine lactylation (Pan-Kla) in AD. The results showed that Pan-Kla protein levels in the hippocampus and frontal cortex tissues of patients with AD were not significantly changed compared with age-matched control participants (Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/JCI184656DS1). Similar to the findings in patients with AD, the Pan-Kla expression levels remained unchanged in the hippocampus and cortex tissues of 6-month-old APP23/PS45 double-transgenic AD model mice compared with age-matched WT mice (Supplemental Figure 1B). Additionally, to observe the localized expression of Pan-Kla in neuronal cells, immunofluorescence staining experiments revealed that Pan-Kla significantly colocalized with microglia (CD11B), astrocytes (GFAP), and neurons (NEUN) in hippocampus tissue sections from 6-month-old WT mice and APP23/PS45 double-transgenic AD mice (Supplemental Figure 1, C–E). This indicates that Pan-Kla is widely expressed in hippocampal neuronal cells of AD mice and may play a potential function in AD.
Next, we focused on detecting the expression level of lactylation modification of APP (APP-Kla) in AD. The results showed that APP-Kla protein levels in the hippocampus and frontal cortex tissues of patients with AD were significantly reduced compared with age-matched participants in the control group (Figure 1, A–D). Similar to the findings in patients with AD, the expression levels of APP-Kla were significantly decreased in the hippocampus and cortex tissues of 6-month-old APP23/PS45 double-transgenic AD model mice compared with age-matched WT mice (Figure 1, E–H). To further explore the APP-Kla without endogenous interference, we constructed APP knockout (APPKO) cell lines in HEK293 cells by CRISPR/Cas9 technology (Figure 1I). The protein expression of APP was almost completely abolished in APPKO cells compared with control (ctrl) cells, indicating a highly efficient APP knockout (Figure 1J). Next, we constructed the APPWT or APPswe695 mutant plasmids (Figure 1K) and transfected into APPKO cell lines. We found that the APP-Kla level was significantly reduced in APPswe695 compared with APPWT (Figure 1L). To more directly detect the expression distribution of APP and Pan-Kla, we performed immunofluorescence assays and found that the colocalization coefficient of APP with Pan-Kla in the APPswe695 group was significantly lower than that in the APPWT group (Figure 1, M and N). Taken together, these results suggest that the expression level of APP-Kla is reduced in AD.
Figure 1Reduced expression level of APP lactylation modification in AD. (A–D) Hippocampus (A and B) and frontal cortex (C and D) tissue lysates were immunoprecipitated with APP antibody, followed by immunoblot analysis with Pan-Kla antibody to detect APP-Kla expression levels in patients with AD and age-matched people in the control group (n = 6 in each group). (E–H) Hippocampus (E and F) and cortex (G and H) tissue lysates were immunoprecipitated with APP antibody, followed by immunoblot analysis with Pan-Kla antibody to detect APP-Kla expression levels in WT and APP23/PS45 mice at the age of 6 months (n = 5 in each group). (I) Genomic DNA sequences of APP locus in APPKO HEK293 cells. (J) The relative protein levels of APP were assessed by Western blot in APPKO cells and HEK293 cells (n = 3 in each group). (K) Sequencing map of the APPWT and APPswe695 mutation site. (L) Cell lysates were immunoprecipitated with APP antibody, followed by immunoblot analysis with Pan-Kla antibody to detect APP-Kla expression levels in APPWT and APPswe695 groups (n = 3 in each group). (M and N) Representative confocal fluorescence images of APP costained with Pan-Kla in APPWT and APPswe695 groups (M), as well as the colocalization of APP with Pan-Kla in multiple confocal images quantified by calculating the Manders’ overlap coefficient (N) (n > 60 cells in each group; scale bars: 5 μm (left) and 1.25 μm (right)). Data were presented as mean ± SEM, *P < 0.05, **P < 0.01, ***P < 0.001 by 2-tailed unpaired Student’s t test (B–D, F, G, J, and N).
APP-K612la reduces APP amyloidogenic processing in vitro. Further mass spectrometry analysis predicted 3 possible lysine sites including APPK354, APPK363, and APPK612, where APP may undergo lactylation modification (Figure 2A and Supplemental Figure 2, A and B). To mimic lactylation or delactylation of APP, we replaced lysine in APPswe695 with threonine (39) (APPK354T, APPK363T, and APPK612T) or glutamine (40) (APPK354Q, APPK363Q, and APPK612Q), respectively (Supplemental Figure 2C and Figure 2, B–D). Subsequently, we constructed the plasmids and transfected into APPKO cell lines. Neither APPK354Q nor APPK354T affected the protein expression levels of APP and CTF-β compared with APPswe695 (Figure 2, E–G). Similarly, both APPK363Q and APPK363T also did not change the protein expression levels of APP and CTF-β (Figure 2, H–J). However, the protein expression levels of CTF-β and sAPP-β, but not APP and its proteolytic enzymes, including BACE1, ADAM10, and PS1 were markedly reduced in APPK612T (
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