Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease
Rikesh M. Rajani(UK Dementia Research Institute), Robert Ellingford(UK Dementia Research Institute), Mariam Hellmuth(UK Dementia Research Institute), Sam Harris(UK Dementia Research Institute), Orjona Taso(UK Dementia Research Institute), David Graykowski(UK Dementia Research Institute), Francesca Kar Wey Lam(UK Dementia Research Institute), Charles Arber(National Hospital for Neurology and Neurosurgery), Emre Fertan(University of Cambridge), John S. H. Danial(University of St Andrews), Matthew Swire(Wolfson Foundation), Marcus Lloyd(Wolfson Foundation), Tatiana A. Giovannucci(National Hospital for Neurology and Neurosurgery), Mathieu Bourdenx(UK Dementia Research Institute), David Klenerman(University of Cambridge), Robert Vassar(Northwestern University), Selina Wray(National Hospital for Neurology and Neurosurgery), Carlo Sala Frigerio(UK Dementia Research Institute), Marc Aurel Busche(UK Dementia Research Institute)
Cited by 42Open Access
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.