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

Rikesh M Rajani; Robert Ellingford; Mariam Hellmuth; Samuel S Harris; Orjona S Taso; David Graykowski; Francesca Kar Wey Lam; Charles Arber; Emre Fertan; John S H Danial; Matthew Swire; Marcus Lloyd; Tatiana A Giovannucci; Mathieu Bourdenx; David Klenerman; Robert Vassar; Selina Wray; Carlo Sala Frigerio; Marc Aurel Busche

doi:10.1371/journal.pbio.3002727

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. eCollection 2024 Jul.

Authors

Rikesh M Rajani¹, Robert Ellingford¹, Mariam Hellmuth¹, Samuel S Harris¹, Orjona S Taso¹, David Graykowski¹, Francesca Kar Wey Lam¹, Charles Arber², Emre Fertan^{3

4}, John S H Danial^{3

4

5}, Matthew Swire⁶, Marcus Lloyd⁶, Tatiana A Giovannucci², Mathieu Bourdenx¹, David Klenerman^{3

4}, Robert Vassar⁷, Selina Wray², Carlo Sala Frigerio¹, Marc Aurel Busche¹

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.

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.

Copyright: © 2024 Rajani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

MeSH terms

Alzheimer Disease* / genetics
Alzheimer Disease* / metabolism
Alzheimer Disease* / pathology
Amyloid beta-Peptides* / metabolism
Animals
Brain / metabolism
Brain / pathology
Disease Models, Animal*
Female
Gene Knock-In Techniques
Humans
Male
Mice
Mice, Transgenic*
Neurons* / metabolism
Oligodendroglia* / metabolism

Substances

Amyloid beta-Peptides
APP protein, mouse
APP protein, human

Grants and funding

R.M.R, D.K., C.S.F. and M.A.B. are supported by the UK Dementia Research Institute through UK DRI Ltd, principally funded by the UK Medical Research Council. M.A.B. is further supported by an UKRI Future Leaders Fellowship (MR/X011038/1) and an NC3Rs studentship grant (NC/W001675/1). S.S.H. is supported by an Alzheimer’s Association International Research Fellowship (AARF-23-1149637). C.A. and S.W. are supported by the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre. M.S. is supported by an MRC Career Development Award (MR/X019977/1). T.A.G. is supported by an Alzheimer’s Association Research Fellowship to Promote Diversity (23AARFD-1029918). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding websites: UK DRI - http://ukdri.ac.uk UKRI/Medical Research Council - https://www.ukri.org/councils/mrc/ NC3Rs - https://www.nc3rs.org.uk NIHR - https://www.uclhospitals.brc.nihr.ac.uk Alzheimer’s Association - https://www.alz.org.