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

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.

Description

Acknowledgements: We thank David Attwell, Siddharthan Chandran, Bart De Strooper, and James Rowland for comments on the manuscript. We thank UK DRI at UCL technical staff Elena Ghirardello and Phillip Muckett for the maintenance of animal colonies and assistance with animal experiments. We thank the Queen Square Brain Bank for Neurological Disorders for provision of human brain tissue samples. The Queen Square Brain Bank is supported by the Reta Lila Weston Institute of Neurological Studies, UCL Queen Square Institute of Neurology. We thank Tanja Kuhlmann and the University of Münster for providing the SON lentivirus. We thank Takashi Saito and Takaomi C. Saido for provision of AppNL-G-F mice. We thank Ulf Neumann and Derya Shimshek from Novartis for providing us with the BACE1 inhibitor NB-360.

Funder: UK Dementia Research Institute; funder-id: http://dx.doi.org/10.13039/501100017510

Funder: National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre

Keywords

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

Journal Title

PLoS Biol

Journal ISSN

1544-9173
1545-7885

Volume Title

22

Publisher

Public Library of Science (PLoS)

Publisher DOI

https://doi.org/10.1371/journal.pbio.3002727

Rights

Attribution 4.0 International

Sponsorship

Medical Research Council (MR/X011038/1)
National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/W001675/1)
Alzheimer's Association (AARF-23 1149637)
Medical Research Council (MR/X019977/1)
Alzheimer’s Association (23AARFD-1029918)

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