2. Academic Validation
  3. Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer's disease

Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer's disease

  • PLoS Biol. 2024 Jul 23;22(7):e3002727. doi: 10.1371/journal.pbio.3002727.
Rikesh M Rajani 1,  Robert Ellingford 1,  Mariam Hellmuth 1,  Samuel S Harris 1,  Orjona S Taso 1,  David Graykowski 1,  Francesca Kar Wey Lam 1,  Charles Arber 2,  Emre Fertan 3 4,  John S H Danial 3 4 5,  Matthew Swire 6,  Marcus Lloyd 6,  Tatiana A Giovannucci 2,  Mathieu Bourdenx 1,  David Klenerman 3 4,  Robert Vassar 7,  Selina Wray 2,  Carlo Sala Frigerio 1,  Marc Aurel Busche 1
Affiliations

Affiliations

  • 1 UK Dementia Research Institute at UCL, University College London, London, United Kingdom.
  • 2 Department of Neurodegenerative Disease, University College London Queen Square Institute of Neurology, London, United Kingdom.
  • 3 Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
  • 4 UK Dementia Research Institute at University of Cambridge, Cambridge, United Kingdom.
  • 5 School of Physics and Astronomy, University of St Andrews, St. Andrews, United Kingdom.
  • 6 Wolfson Institute for Biomedical Research, University College London, London, United Kingdom.
  • 7 Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
PMID: 39042667 DOI: 10.1371/journal.pbio.3002727
Abstract

Reduction of amyloid beta (Aβ) has been shown to be effective in treating Alzheimer's disease (AD), but the underlying assumption that neurons are the main source of pathogenic Aβ is untested. Here, we challenge this prevailing belief by demonstrating that oligodendrocytes are an important source of Aβ in the human brain and play a key role in promoting abnormal neuronal hyperactivity in an AD knock-in mouse model. We show that selectively suppressing oligodendrocyte Aβ production improves AD brain pathology and restores neuronal function in the mouse model in vivo. Our findings suggest that targeting oligodendrocyte Aβ production could be a promising therapeutic strategy for treating AD.

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