A Question of Origins: Non-neuronal Sources of Amyloid-β

Amyloid-β (Aβ) plaques and neurofibrillary tau tangles are hallmarks of Alzheimer's disease (AD). While the intracellular localization of tau tangles within neurons nominates them as the primary producers of tau, the cellular origin of Aβ is less clear as plaques accumulate extracellularly. Neurons have been considered the sole source of Aβ, leading to the generation of many AD animal models expressing familial AD protein variants specifically in neurons. However, emerging evidence showed that non-neuronal cells abundantly express amyloid precursor protein (APP) and its processing machinery. Among these, oligodendrocytes (OLs) exhibit the highest expression of amyloidogenic components, produce Aβ, and contribute to plaque burden in vivo. Here, we highlight reports on non-neuronal Aβ production in the context of AD and the function of APP processing in these cells. Understanding Aβ processing in non-neuronal cells might enable the identification of novel therapeutic targets, especially in humans whose brain structures differ greatly from animal models.