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Peer-reviewedCC BY-NC-NDNature Aging

Reduced ULK1 links impaired autophagy and mitophagy to Alzheimer’s disease pathology

  • Jun‐Ping Pan1,2,3
  • Ping-Jie Wang2,4
  • Jianying Zhang1,5
  • Anne‐Brita Knapskog6
  • Leiv Otto Watne7,6,8
  • He-Ling Wang1,2
  • Mariá José Lagartos-Donate1
  • Sofie Lautrup1
  • Li-Peng Mao2,9
  • Qian Wang10,4
  • Zhi‐Peng Ling2
  • Shi-qi Zhang1
28 more authors
  • Tomas Schmauck‐Medina1
  • Ruixue Ai1
  • Trine Holt Edwin6
  • Tianjiao Zhang11
  • Ingvild Tina Saltvedt12,13
  • Rannveig Sakshaug Eldholm12,13
  • Annabel Smith14
  • Kateřina Veverová15
  • Domenica Caponio1
  • Asgeir Kobro‐Flatmoen16
  • 庞欢欢17
  • Zijian Wang2
  • Haoyun Wang1,2
  • Li-juan Gao2
  • Nathalie Bodd Halaas6,18
  • Garry Wong11
  • Martin Vyhnálek15
  • Oscar Junhong Luo9
  • William A. McEwan14
  • Jon Storm‐Mathisen19,20
  • Li Gan21
  • Zeping Hu17
  • Henrik Zetterberg22,23,24,25,26,27
  • Menno P. Witter16
  • Dag Aarsland28,29
  • Geir Selbæk6,30,31
  • Guobing Chen32,33,34
  • Evandro Fei Fang35,36,37,38,39
39 affiliations
  1. 1Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway
  2. 2Department of Microbiology and Immunology, School of Medicine; Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, China
  3. 3Guangdong Second Provincial General Hospital, Postdoctoral Research Station of Basic Medicine, School of Medicine, Jinan University, Guangzhou, China
  4. 4Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
  5. 5Xiangya School of Stomatology, Central South University, Changsha, China
  6. 6Department of Geriatric Medicine, Oslo University Hospital (Ullevaal), Oslo, Norway
  7. 7Department of Geriatric Medicine, Akershus University Hospital, Lørenskog, Norway
  8. 8Institute of Clinical Medicine Campus Ahus, University of Oslo, Lørenskog, Norway
  9. 9Department of Systems Biomedical Sciences, School of Medicine, Jinan University, Guangzhou, China
  10. 10Department of Geriatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
  11. 11Centre for Reproduction, Development and Aging, Faculty of Health Sciences, University of Macau, Macau, China
  12. 12Department of Geriatrics, St. Olavs Hospital, University Hospital of Trondheim, Trondheim, Norway
  13. 13Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway
  14. 14UK Dementia Research Institute, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
  15. 15Memory Clinic, Department of Neurology, Charles University, 2nd Faculty of Medicine and Motol University Hospital, Prague, Czech Republic
  16. 16Kavli Institute for Systems Neuroscience, K.G. Jebsen Centre for Alzheimer's Disease, Centre for Algorithms in the Cortex, Egil and Pauline Braathen and Fred Kavli Centre for Cortical Microcircuits, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
  17. 17School of Pharmaceutical Sciences, Tsinghua-Peking Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing, China
  18. 18Institute of Clinical Medicine, Campus Ullevål, University of Oslo, Oslo, Norway
  19. 19Synaptic Neurochemistry and Amino Acid Transporters Labs, Division of Anatomy, Department of Molecular Medicine, Institute of Basic Medical Sciences (IMB) and Healthy Brain Aging Centre (SERTA), University of Oslo, Oslo, Norway
  20. 20The Norwegian Centre on Healthy Ageing (NO-Age) and The Norwegian National Anti-Alzheimer's Disease (NO-AD) Networks, Oslo, Norway
  21. 21Helen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
  22. 22Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  23. 23Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK
  24. 24Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
  25. 25Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China
  26. 26UK Dementia Research Institute at UCL, London, UK
  27. 27Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
  28. 28Centre for Age-Related Medicine (SESAM), Stavanger University Hospital, Stavanger, Norway
  29. 29Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
  30. 30Faculty of Medicine, University of Oslo, Oslo, Norway
  31. 31Norwegian National Centre for Aging and Health, Vestfold Hospital Trust, Tønsberg, Norway
  32. 32Department of Microbiology and Immunology, School of Medicine; Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, China. [email protected]
  33. 33Guangdong Second Provincial General Hospital, Postdoctoral Research Station of Basic Medicine, School of Medicine, Jinan University, Guangzhou, China. [email protected]
  34. 34Zhuhai Institute of Jinan University, Jinan University, Zhuhai, China. [email protected]
  35. 35Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway. [email protected]
  36. 36Department of Geriatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. [email protected]
  37. 37Department of Microbiology and Immunology, School of Medicine; Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, China. [email protected]
  38. 38Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. [email protected]
  39. 39The Norwegian Centre on Healthy Ageing (NO-Age) and The Norwegian National Anti-Alzheimer's Disease (NO-AD) Networks, Oslo, Norway. [email protected]
Open at sourceDOICite

Abstract

ULK1 (Atg1) initiates macroautophagy and mitophagy, which support neuronal growth and survival, yet how this pathway is disrupted in aging and Alzheimer’s disease (AD) remains unclear. Here we report reduced ULK1 in serum and cerebrospinal fluid during aging in cognitively unimpaired participants from the COGNORM study (n = 75) and in patients with AD from the NorCog Memory Clinic Cohort (n = 316). In AD mice, ULK1 overexpression stimulates autophagic flux, reduces AD pathology and delays cognitive decline alongside increased phagocytic degradation of amyloid-β, reduced tauopathy and improved mitochondrial quality. Mechanistically, ULK1 upregulation increases autophagy and PINK1-, FUNDC1- and AMBRA1-associated mitophagy; higher autophagy and mitophagy increase cellular NAD+, which in turn deacetylates acetylated-Tau174 via the NAD+–SIRT1 axis, leading to reduced tauopathy. Using in vitro tau seeding assays and a Caenorhabditis elegans tau model, we validate the efficacy of ULK1 activators in inhibiting tauopathy. We propose that age-related decline in ULK1 leads to autophagy and mitophagy impairment and increases the progression of AD and identify ULK1 as a potential therapeutic target. Autophagic activity has a protective role in Alzheimer’s disease in mice. Here the authors investigate the role of autophagy-initiating protein ULK1 and report that its overexpression stimulates autophagic flux, reduces amyloid and tau pathology and delays cognitive decline.

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Cite

BibTeXRIS
BibTeX
@article{pan2026reduced,
  title = {{Reduced ULK1 links impaired autophagy and mitophagy to Alzheimer’s disease pathology}},
  author = {Jun‐Ping Pan and Ping-Jie Wang and Jianying Zhang and Anne‐Brita Knapskog and Leiv Otto Watne and He-Ling Wang and Mariá José Lagartos-Donate and Sofie Lautrup and Li-Peng Mao and Qian Wang and Zhi‐Peng Ling and Shi-qi Zhang and Tomas Schmauck‐Medina and Ruixue Ai and Trine Holt Edwin and Tianjiao Zhang and Ingvild Tina Saltvedt and Rannveig Sakshaug Eldholm and Annabel Smith and Kateřina Veverová and Domenica Caponio and Asgeir Kobro‐Flatmoen and 庞欢欢 and Zijian Wang and Haoyun Wang and Li-juan Gao and Nathalie Bodd Halaas and Garry Wong and Martin Vyhnálek and Oscar Junhong Luo and William A. McEwan and Jon Storm‐Mathisen and Li Gan and Zeping Hu and Henrik Zetterberg and Menno P. Witter and Dag Aarsland and Geir Selbæk and Guobing Chen and Evandro Fei Fang},
  journal = {Nature Aging},
  year = {2026},
  month = may,
  doi = {10.1038/s43587-026-01108-z},
  url = {https://doi.org/10.1038/s43587-026-01108-z},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Reduced ULK1 links impaired autophagy and mitophagy to Alzheimer’s disease pathology
AU  - Jun‐Ping Pan
AU  - Ping-Jie Wang
AU  - Jianying Zhang
AU  - Anne‐Brita Knapskog
AU  - Leiv Otto Watne
AU  - He-Ling Wang
AU  - Mariá José Lagartos-Donate
AU  - Sofie Lautrup
AU  - Li-Peng Mao
AU  - Qian Wang
AU  - Zhi‐Peng Ling
AU  - Shi-qi Zhang
AU  - Tomas Schmauck‐Medina
AU  - Ruixue Ai
AU  - Trine Holt Edwin
AU  - Tianjiao Zhang
AU  - Ingvild Tina Saltvedt
AU  - Rannveig Sakshaug Eldholm
AU  - Annabel Smith
AU  - Kateřina Veverová
AU  - Domenica Caponio
AU  - Asgeir Kobro‐Flatmoen
AU  - 庞欢欢
AU  - Zijian Wang
AU  - Haoyun Wang
AU  - Li-juan Gao
AU  - Nathalie Bodd Halaas
AU  - Garry Wong
AU  - Martin Vyhnálek
AU  - Oscar Junhong Luo
AU  - William A. McEwan
AU  - Jon Storm‐Mathisen
AU  - Li Gan
AU  - Zeping Hu
AU  - Henrik Zetterberg
AU  - Menno P. Witter
AU  - Dag Aarsland
AU  - Geir Selbæk
AU  - Guobing Chen
AU  - Evandro Fei Fang
PY  - 2026
DA  - 2026/05/14
JO  - Nature Aging
DO  - 10.1038/s43587-026-01108-z
UR  - https://doi.org/10.1038/s43587-026-01108-z
AB  - ULK1 (Atg1) initiates macroautophagy and mitophagy, which support neuronal growth and survival, yet how this pathway is disrupted in aging and Alzheimer’s disease (AD) remains unclear. Here we report reduced ULK1 in serum and cerebrospinal fluid during aging in cognitively unimpaired participants from the COGNORM study (n = 75) and in patients with AD from the NorCog Memory Clinic Cohort (n = 316). In AD mice, ULK1 overexpression stimulates autophagic flux, reduces AD pathology and delays cognitive decline alongside increased phagocytic degradation of amyloid-β, reduced tauopathy and improved mitochondrial quality. Mechanistically, ULK1 upregulation increases autophagy and PINK1-, FUNDC1- and AMBRA1-associated mitophagy; higher autophagy and mitophagy increase cellular NAD+, which in turn deacetylates acetylated-Tau174 via the NAD+–SIRT1 axis, leading to reduced tauopathy. Using in vitro tau seeding assays and a Caenorhabditis elegans tau model, we validate the efficacy of ULK1 activators in inhibiting tauopathy. We propose that age-related decline in ULK1 leads to autophagy and mitophagy impairment and increases the progression of AD and identify ULK1 as a potential therapeutic target. Autophagic activity has a protective role in Alzheimer’s disease in mice. Here the authors investigate the role of autophagy-initiating protein ULK1 and report that its overexpression stimulates autophagic flux, reduces amyloid and tau pathology and delays cognitive decline.
SN  - 2662-8465
ER  -