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

Funding: 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).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.Peer reviewe

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

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/10.13039/501100017510Funder: National Institute for Health and Care Research University College London Hospitals Biomedical Research CentreReduction 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