Oligodendrocytes are a major source of amyloid beta (Aβ) and play a key role in promoting neuronal dysfunction in Alzheimer’s disease (AD), according to a study published July 23, 2024 in the open-access journal PLOS Biology by Rikesh Rajani and Marc Aurel Busche of the Dementia Research Institute, University College London, and colleagues.
Alzheimer’s disease is a devastating neurodegenerative disorder affecting millions of people worldwide. The accumulation of Aβ (peptides consisting of 36 to 43 amino acids) is a critical early sign of the disease. Recent clinical trials demonstrating a slowing of cognitive and functional decline in people with Alzheimer’s disease receiving treatment with anti-Aβ antibodies reinforce the important role of the latter in the disease process. Despite the key cellular effects of Aβ and its essential role in Alzheimer’s disease, the traditional assumption that neurons are the main source of toxic Aβ in the brain remains unproven.
In the study, Rajani and Busche demonstrated that non-neuronal brain cells called oligodendrocytes produce Aβ. Furthermore, they showed that selectively suppressing Aβ production in oligodendrocytes in a mouse model of AD is sufficient to rescue abnormal neuronal hyperactivity. The results provide evidence for a critical role of oligodendrocyte-derived Aβ for early neuronal dysfunction in AD. Taken together, the findings suggest that targeting oligodendrocyte Aβ production could be a promising therapeutic strategy for treating AD.
According to the authors, the functional rescue is remarkable given the relatively modest reduction in plaque burden that results from blocking oligodendrocyte Aβ production, whereas blocking neuronal Aβ production leads to near-total clearance of plaques, another hallmark of the disease. This small contribution of oligodendrocytes to plaque burden might suggest that a major effect of oligodendrocyte-derived Aβ is to promote neuronal dysfunction.
Together with data showing increased numbers of Aβ-producing oligodendrocytes in the deeper cortical layers of AD brains, these results indicate that oligodendrocyte-derived Aβ plays a pivotal role in the early deterioration of neural circuits in AD, which has important implications for how the disease progresses and its treatment. The increased number of oligodendrocytes in AD brains also raises the intriguing possibility that these cells could potentially compensate for reduced Aβ production due to neuronal loss as the disease progresses.
The authors add: “Our study challenges the long-held belief that neurons are the exclusive source of amyloid beta in the brain, one of the key toxic proteins that accumulate in Alzheimer’s disease. In fact, we show that oligodendrocytes, the myelinating cells of the central nervous system, can also produce significant amounts of amyloid beta that impairs neuronal function, and suggests that targeting these cells may be a promising new strategy for treating Alzheimer’s disease.”