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; Mikael Simons

doi:10.1371/journal.pbio.3002727

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^*, Mikael Simons (Editor)

^*Corresponding author for this work

School of Physics and Astronomy

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	e3002727
Number of pages	30
Journal	PLoS Biology
Volume	22
Issue number	7
Early online date	23 Jul 2024
DOIs	https://doi.org/10.1371/journal.pbio.3002727
Publication status	E-pub ahead of print - 23 Jul 2024

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Rajani-2024-Selective-suppression-PBIO-3002727-CCBY
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.
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Rajani, R. M., Ellingford, R., Hellmuth, M., Harris, S. S., Taso, O. S., Graykowski, D., Lam, F. K. W., Arber, C., Fertan, E., Danial, J. S. H., Swire, M., Lloyd, M., Giovannucci, T. A., Bourdenx, M., Klenerman, D., Vassar, R., Wray, S., Sala Frigerio, C., Busche, M. A., & Simons, M. (Ed.) (2024). Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease. PLoS Biology, 22(7), Article e3002727. Advance online publication. https://doi.org/10.1371/journal.pbio.3002727

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title = "Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer{\textquoteright}s disease",

abstract = "Reduction of amyloid beta (Aβ) has been shown to be effective in treating Alzheimer{\textquoteright}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.",

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

note = "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{\textquoteright}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{\textquoteright}s Association Research Fellowship to Promote Diversity (23AARFD-1029918).",

year = "2024",

month = jul,

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doi = "10.1371/journal.pbio.3002727",

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Rajani, RM, Ellingford, R, Hellmuth, M, Harris, SS, Taso, OS, Graykowski, D, Lam, FKW, Arber, C, Fertan, E, Danial, JSH, Swire, M, Lloyd, M, Giovannucci, TA, Bourdenx, M, Klenerman, D, Vassar, R, Wray, S, Sala Frigerio, C, Busche, MA & Simons, M (ed.) 2024, 'Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease', PLoS Biology, vol. 22, no. 7, e3002727. https://doi.org/10.1371/journal.pbio.3002727

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T1 - Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease

AU - Rajani, Rikesh M.

AU - Ellingford, Robert

AU - Hellmuth, Mariam

AU - Harris, Samuel S.

AU - Taso, Orjona S.

AU - Graykowski, David

AU - Lam, Francesca Kar Wey

AU - Arber, Charles

AU - Fertan, Emre

AU - Danial, John S. H.

AU - Swire, Matthew

AU - Lloyd, Marcus

AU - Giovannucci, Tatiana A.

AU - Bourdenx, Mathieu

AU - Klenerman, David

AU - Vassar, Robert

AU - Wray, Selina

AU - Sala Frigerio, Carlo

AU - Busche, Marc Aurel

A2 - Simons, Mikael

N1 - 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).

PY - 2024/7/23

Y1 - 2024/7/23

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pbio.3002727

DO - 10.1371/journal.pbio.3002727

M3 - Article

SN - 1544-9173

VL - 22

JO - PLoS Biology

JF - PLoS Biology

IS - 7

M1 - e3002727

ER -

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

Abstract

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