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Degradation of FA reduces Aβ neurotoxicity and Alzheimer-related phenotypes

Molecular Psychiatry volume 26, pages 5578–5591 (2021)Cite this article

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Abstract

Dysregulation of formaldehyde (FA) has been implicated in the development of Alzheimer’s Disease (AD). Elevated FA levels in Alzheimer’s patients and animal models are associated with impaired cognitive functions. However, the exact role of FA in AD remains unknown. We now identified that oxidative demethylation at serine8/26 of amyloid-beta protein (Aβ) induced FA generation and FA cross-linked with the lysine28 residue in the β-turn of Aβ monomer to form Aβ dimers, and then accelerated Aβ oligomerization and fibrillogenesis in vitro. However, Aβ42 mutation in serine8/26, lysine28 abolished Aβ self-aggregation. Furthermore, Aβ inhibited the activity of formaldehyde dehydrogenase (FDH), the enzyme for FA degradation, resulting in FA accumulation. In turn, excess of FA stimulated Aβ aggregation both in vitro and in vivo by increasing the formation of Aβ oligomers and fibrils. We found that degradation of FA by formaldehyde scavenger-NaHSO3 or coenzyme Q10 reduced Aβ aggregation and ameliorated the neurotoxicity, and improved the cognitive performance in APP/PS1 mice. Our study provides evidence that endogenous FA is essential for Aβ self-aggregation and scavenging FA could be an effective strategy for treating AD.

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Fig. 1: Aβ42-induced FA generation through the oxidative demethylation of serine residues.
Fig. 2: Aβ interacted with FDH and inhibited FDH activity, leading to FA accumulation.
Fig. 3: FA triggered Aβ oligomeriztion and fibrillogenesis by crosslinking with lysine residues.
Fig. 4: FA stimulated the aggregation of Aβ with the mutants.
Fig. 5: FA facilitated Aβ aggregation and exacerbated Aβ-induced neurotoxicity in APP/PS1 mice.
Fig. 6: Degradation of FA reduced Aβ aggregation and ameliorated memory deficits in APP/PS1 mice.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Prof. Lei Liu of Capital Medical University for his comments. This work was supported by the National Natural Science Foundation of China (82071214); the Beijing Natural Science Foundation of China (7172022); the Scientific Research Common Program of Beijing Municipal Commission of Education (KM201510025014); the Major Projects Fund of Beijing Institute for Brain Disorders (ZD2015-08); and the Canadian Institutes of Health Research (CIHR) Project Grant PJT-166127 (to WS). WS was the holder of the Tier 1 Canada Research Chair in Alzheimer’s Disease.

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Author notes

  1. These authors contributed equally: Xuechao Fei, Yun Zhang, Yufei Mei, Xiangpei Yue

Authors and Affiliations

  1. Alzheimer’s disease Center, Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, 100069, Beijing, China

    Xuechao Fei, Yufei Mei, Xiangpei Yue, Wenjing Jiang, Li Ai, Rongqiao He & Zhiqian Tong

  2. Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, 100053, Beijing, China

    Yun Zhang & Weihong Song

  3. Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada

    Yun Zhang & Weihong Song

  4. School of Basic Medical Sciences, Zhejiang University, Hangzhou, 310058, China

    Yufei Mei

  5. Center for Cognitive Disorders, Beijing Geriatric Hospital, 100095, Beijing, China

    Wenjing Jiang & Jihui Lyv

  6. Chinese institute of Rehabilitation Science, China Rehabilitation Research Center, Beijing Key Laboratory of Neural Injury and Rehabilitation, 100068, Beijing, China

    Yan Yu

  7. Central Laboratory, Shantou University Medical College, Guangdong, 515041, China

    Hongjun Luo, Hui Li & Wenhong Luo

  8. Section of Environmental Biomedicine, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Sciences, Central China Normal University, Wuhan, 430079, China

    Xu Yang

  9. State Key Lab of Brain and Cognitive Science and Key Lab of Mental Health, IBP, UCAS, Beijing, China

    Rongqiao He

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Contributions

WS and ZT conceived and designed the study and supervised all analyses. XF, YZ, YM, XY, WJ, LA, YY, HL, HL, WL, XY, JL and RH performed experiments. WS and ZT analyzed and contributed reagents /materials /analysis tools; XF, YZ, WS and ZT wrote the manuscript. All authors reviewed the manuscript.

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Correspondence to Weihong Song or Zhiqian Tong.

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Fei, X., Zhang, Y., Mei, Y. et al. Degradation of FA reduces Aβ neurotoxicity and Alzheimer-related phenotypes. Mol Psychiatry 26, 5578–5591 (2021). https://doi.org/10.1038/s41380-020-00929-7

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