Article Text

Original research
Molecules of senescent glial cells differentiate Alzheimer’s disease from ageing
  1. Linbin Dai1,2,3,
  2. Feng Gao1,2,
  3. Qiong Wang1,2,
  4. Xinyi Lv1,2,
  5. Zhaozhao Cheng1,2,
  6. Yan Wu1,2,
  7. Xianliang Chai1,2,
  8. Henrik Zetterberg4,5,6,7,8,
  9. Kaj Blennow4,5,
  10. Allan I Levey9,
  11. Jiong Shi1,2,10,
  12. Yong Shen1,2,3,11,12
  13. On behalf of CANDI Consortium
  1. 1 Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People's Republic of China
  2. 2 Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People's Republic of China
  3. 3 Neurodegenerative Disorder Research Center, School of Life Sciences, Division of Life Sciences and Medicine, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, People's Republic of China
  4. 4 Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
  5. 5 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  6. 6 Department of Neurodegenerative Disease,UCL Institute of Neurology, Queen Square, London, UK
  7. 7 UK Dementia Research Institute at UCL, London, UK
  8. 8 Hong Kong Center for Neurodegenerative Diseases, Hong Kong, People's Republic of China
  9. 9 Department of Neurology, Goizueta Alzheimer's Disease Research Center, Emory University, Atlanta, Georgia, USA
  10. 10 China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, People's Republic of China
  11. 11 Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology, Hefei, Anhui, China
  12. 12 Centre for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China
  1. Correspondence to Professor Yong Shen, Neurodegenerative Disorder Research Centre, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, Anhui, China; yongshen{at}ustc.edu.cn

Abstract

Background Ageing is a major risk factor for Alzheimer’s disease (AD), which is accompanied by cellular senescence and thousands of transcriptional changes in the brain.

Objectives To identify the biomarkers in the cerebrospinal fluid (CSF) that could help differentiate healthy ageing from neurodegenerative processes.

Methods Cellular senescence and ageing-related biomarkers were assessed in primary astrocytes and postmortem brains by immunoblotting and immunohistochemistry. The biomarkers were measured in CSF samples from the China Ageing and Neurodegenerative Disorder Initiative cohort using Elisa and the multiplex Luminex platform.

Results The cyclin-dependent kinase inhibitors p16/p21-positive senescent cells in human postmortem brains were predominantly astrocytes and oligodendrocyte lineage cells, which accumulated in AD brains. CCL2, YKL-40, HGF, MIF, S100B, TSP2, LCN2 and serpinA3 are biomarkers closely related to human glial senescence. Moreover, we discovered that most of these molecules, which were upregulated in senescent glial cells, were significantly elevated in the AD brain. Notably, CSF YKL-40 (β=0.5412, p<0.0001) levels were markedly elevated with age in healthy older individuals, whereas HGF (β=0.2732, p=0.0001), MIF (β=0.33714, p=0.0017) and TSP2 (β=0.1996, p=0.0297) levels were more susceptible to age in older individuals with AD pathology. We revealed that YKL-40, TSP2 and serpinA3 were useful biomarkers for discriminating patients with AD from CN individuals and non-AD patients.

Discussion Our findings demonstrated the different patterns of CSF biomarkers related to senescent glial cells between normal ageing and AD, implicating these biomarkers could identify the road node in healthy path off to neurodegeneration and improve the accuracy of clinical AD diagnosis, which would help promote healthy ageing.

  • ALZHEIMER'S DISEASE
  • NEUROPATHOLOGY

Data availability statement

Data are available on reasonable request. The data that support the findings of this study are available from the corresponding authors on reasonable request.

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Data availability statement

Data are available on reasonable request. The data that support the findings of this study are available from the corresponding authors on reasonable request.

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Footnotes

  • LD and FG contributed equally.

  • Contributors YS is Guarantor of the study.

    YS, FG and LD contributed to the conception and design of the study. FG, LD, XL, ZC, YW, QW, XC, QW and JS contributed to the acquisition and analysis of data. YS, FG, LD, HZ, KB and AIL contributed to drafting the text or preparing the figures.

  • Funding This work was supported by the National Key Plan for Scientific Research and Development of China (2020YFA0509304), the Chinese Academy of Sciences (QYZDY-SSW-SMC012 and XDB39000000), the National Natural Sciences Foundation of China (31530089 and 82030034) and the Fundamental Research Funds for the Central Universities (YD2070002003).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.