Alzheimer’s Therapies Could Target Aβ Production by Oligodendrocytes, Not Just Neurons

The results of preclinical studies headed by investigators at the UK Dementia Research Institute at University College London, and colleagues, suggest that non-neuronal brain cells called oligodendrocytes are an important source of amyloid beta (Aβ) and play a key role in promoting neuronal dysfunction in a mouse model of Alzheimer’s disease (AD). The team’s studies in live mice also showed that selectively suppressing oligodendrocyte Aβ production improved AD brain pathology and restored neuronal function. The collective results indicate that targeting oligodendrocyte Aβ production could be a promising therapeutic strategy for treating AD.

Rikesh Rajani, PhD, Marc Aurel Busche, MD, PhD, and colleagues reported on their findings in PLOS Biology, in a paper titled “Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease.” In their report the researchers concluded, “… we provide evidence for a critical role of oligodendrocyte-derived Aβ for early neuronal dysfunction in AD.”

Alzheimer’s disease is a devastating neurodegenerative disorder affecting millions of people worldwide, the authors wrote. Accumulation of Aβ—peptides consisting of 36 to 43 amino acids—is an early critical hallmark of the disease. “Recent clinical trials demonstrating a slowing of cognitive and functional decline in individuals with AD treated with anti-Aβ antibodies indeed reinforce the important role of Aβ in AD pathophysiology,” the team stated.

Despite the key cellular effects of Aβ and its essential role in AD, the traditional assumption that neurons are the primary source of toxic Aβ in the brain has remained untested, the team continued. Rajani and Busche carried out studies in human postmortem brain tissue and in human induced pluripotent stem cell (iPSC)-derived oligodendrocytes, to demonstrate that oligodendrocytes can produce Aβ. Interestingly, the results, the investigators noted, “… suggest that Aβ produced by oligodendrocytes has a higher propensity for aggregation than neuron-derived Aβ.”

The team further demonstrated that selectively suppressing Aβ production in oligodendrocytes in an AD mouse model is sufficient to rescue abnormal neuronal hyperactivity. “Our results that targeted suppression of Aβ production in oligodendrocytes can rescue neuronal hyperactivity, even without the complete elimination of plaques, indicated that soluble Aβ species produced by oligodendrocytes may in fact contribute to early neuronal dysfunction in the AD brain,” they stated. Further studies in mice then indicated that oligodendrocyte-derived Aβ is sufficient to promote neuronal hyperactivity, even in the absence of Aβ from any other cellular source.

According to the authors, the functional rescue is remarkable given the relatively modest reduction in plaque load that results from blocking oligodendrocyte Aβ production, while blocking neuronal Aβ production leads to a near elimination of plaques—another hallmark of the disease. “This small contribution of oligodendrocytes to plaque load could suggest that a main effect of oligodendrocyte-derived Aβ is to promote neuronal dysfunction,” the authors pointed out. “Rather than being plaque dependent, the effects of Aβ on neuronal activity and synaptic function often stem from soluble aggregates similar to those we see produced in much greater numbers by oligodendrocytes.”

Together with the data showing an increased number of Aβ-producing oligodendrocytes in deeper cortical layers of the brains of individuals with AD, “… these results indicate that oligodendrocyte-derived Aβ plays a pivotal role in the early impairment of neuronal circuits in AD, which has important implications for how we consider and treat the disease,” the investigators stated.

The increased number of oligodendrocytes in human AD brains also raises the intriguing possibility that these cells could potentially offset reduced Aβ production due to neuronal loss as the disease progresses. The authors say their study findings challenge the long-held belief that neurons are the exclusive source of amyloid beta in the brain, and shows that oligodendrocytes, the myelinating cells of the central nervous system, can also produce significant amounts of amyloid beta which impairs neuronal function.

The collective results provide evidence that oligodendrocyte-derived Aβ may play a key role in early neuronal dysfunction in AD, and also suggest that targeting oligodendrocyte Aβ production could be a promising therapeutic strategy for treating AD.

The investigators further pointed out that clinical trials testing anti-Aβ antibody therapies targeting plaques have demonstrated adverse effects, while studies evaluating BACE inhibition as an approach to reducing Aβ have failed to demonstrate similar beneficial effects. “Thus, to circumvent such unwanted effects, we propose that blocking Aβ production specifically in oligodendrocytes, for example, by employing oligodendrocyte-targeting AAVs, may constitute a promising novel target for treating AD,” they wrote.