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

Abstract

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.

Association of Retromer Deficiency and Tau Pathology in Down Syndrome

“…As such, retromer has emerged as a key player in protein trafficking and homeostasis, and its dysfunction is implicated in several neurodegenerative diseases. 16 We recently reported that protein levels of the retromer recognition core, VPS35, VPS26, and VPS29, are decreased and negatively correlate with the amount of brain amyloidosis in patients with Down syndrome. 8 In the present study, we extend this analysis to include tau pathology in the same cohort.…”

Endosomal Recycling Defects and Neurodevelopmental Disorders

“…A dysfunction of retromer is also suggested in Down syndrome (DS) [ 19 ]. Individuals with DS have an increased risk of developing AD: more than 60% of individuals with DS will show clinical features of AD by 40 to 50 years of age [ 20 ].…”

Rodent Modeling of Alzheimer's Disease in Down Syndrome: In vivo and ex vivo Approaches

“…However, use of another γ-secretase inhibitor in the same model was thought to improve cognition and neuron loss via an alternative mechanism by modulating the Sonic-hedgehog pathway, which is also altered in DS (Stagni et al, 2017 ). Furthermore, γ-secretase inhibition leads to increased production of CTFs (Netzer et al, 2010 ), which have been implicated in enlargement of endosomes in DS, contributing to perturbed neuronal transport (Filippone and Praticò, 2021 ). Given recent data indicating particularly highly elevated levels of this fragment in people with DS and preclinical DS mouse models (Lana-Elola et al, 2021 ), modulation of γ-secretase in people who have DS should be approached with caution.…”