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DEMENTIA

The phosphorylation cascade hypothesis of Alzheimer’s disease

Nature Aging volume 1, pages 498–499 (2021)Cite this article

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Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ)-induced phosphorylation of the axon-stabilizing tau protein, which causes neurodegeneration. Here, Morshed et al. show that deregulated phosphorylation in AD also affects other proteins and cell types in the brain, suggesting that the tau-centric view on Aβ toxicity should be revised.

Recent large-scale proteomics studies have revealed neuronal, astrocytic and microglial protein profile changes in Alzheimer’s disease (AD) brains and biofluids1,2. Still, our understanding of how these changes relate to the pathognomonic amyloid-β (Aβ) pathology of the disease and through which signaling pathways they are induced remains incomplete. In this issue of Nature Aging, Morshed et al.3 take a deep dive into the phosphoproteome of human AD brains and uncover several Aβ-associated dysregulated kinase networks that may underlie many of the protein changes reported, shedding new light on the complex cellular phase of the disease.

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Fig. 1: Kinome map of all kinases with phosphopeptides that were significantly associated with tau or oligodendrocyte cluster centroids.

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Acknowledgements

Work in the authors’ laboratories is supported by the Swedish Research Council, the European Research Council, Swedish State Support for Clinical Research (ALFGBG), the Knut and Alice Wallenberg Foundation, and UK Dementia Research Institute at UCL. H.Z. is a Wallenberg Scholar.

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Authors and Affiliations

  1. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden

    Gunnar Brinkmalm & Henrik Zetterberg

  2. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden

    Gunnar Brinkmalm & Henrik Zetterberg

  3. Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK

    Henrik Zetterberg

  4. UK Dementia Research Institute at UCL, London, UK

    Henrik Zetterberg

Authors
  1. Gunnar Brinkmalm
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  2. Henrik Zetterberg
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Corresponding authors

Correspondence to Gunnar Brinkmalm or Henrik Zetterberg.

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Competing interests

H.Z. has served at scientific advisory boards for Alector, Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies and CogRx; has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure and Biogen; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside of submitted work). G.B. declares no competing interests.

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Brinkmalm, G., Zetterberg, H. The phosphorylation cascade hypothesis of Alzheimer’s disease. Nat Aging 1, 498–499 (2021). https://doi.org/10.1038/s43587-021-00077-9

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  • DOI: https://doi.org/10.1038/s43587-021-00077-9

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