Endosome Dysregulation in Down Syndrome: A Potential Contributor to Alzheimer Disease Pathology

Intracellular protein trafficking via the endosomes plays a key role in the maintenance of normal neuronal function. Although many diseases of the central nervous system exhibit specific pathological hallmarks, abnormalities of the endosome system are common traits for several of them, including Alzheimer disease (AD). Three main routes originate from the endosomes: the recycling, degradation, and retrograde pathways. Studies have shown that the majority of Down syndrome subjects develop AD pathology and manifest altered morphology and number of endosomes, and abnormalities in lysosome acidification and exosome secretion, suggesting that dysfunction of one of these pathways could play a functional role in the AD-like phenotype of the syndrome. Two of the major endosomal routes are mediated by the retromer complex, a multimeric system responsible for transport of cargo from the endosome to the trans-Golgi network or to the cell membrane. Recently, a new endosome system structurally related to the retromer, called “retriever,” has been reported. Whereas we know a great deal about the neuropathophysiology of the retromer complex, no precise pathogenic role for the retriever has yet been identified. Here, we will review the neurobiology of the endosome system and its role as key player in the development of AD-like pathology in Down syndrome. Additionally, we will discuss current knowledge on these two main endosome systems, retromer and retriever, and their potential as novel therapeutic targets. ANN NEUROL 2021;90:4–14.