Transmissible Endosomal Intoxication: A Balance between Exosomes and Lysosomes at the Basis of Intercellular Amyloid Propagation

Abstract

In Alzheimer′s disease (AD), endolysosomal dysfunctions are amongst the earliest cellular features to appear. Each organelle of the endolysosomal system, from the multivesicular body (MVB) to the lysosome, contributes to the homeostasis of amyloid precursor protein (APP) cleavage products including β-amyloid (Aβ) peptides. Hence, this review will attempt to disentangle how changes in the endolysosomal system cumulate to the generation of toxic amyloid species and hamper their degradation. We highlight that the formation of MVBs and the generation of amyloid species are closely linked and describe how the molecular machineries acting at MVBs determine the generation and sorting of APP cleavage products towards their degradation or release in association with exosomes. In particular, we will focus on AD-related distortions of the endolysomal system that divert it from its degradative function to favour the release of exosomes and associated amyloid species. We propose here that such an imbalance transposed at the brain scale poses a novel concept of transmissible endosomal intoxication (TEI). This TEI would initiate a self-perpetuating transmission of endosomal dysfunction between cells that would support the propagation of amyloid species in neurodegenerative diseases.

Opposing functions for retromer and Rab11 in extracellular vesicle traffic at presynaptic terminals

“…We next investigated the mechanisms by which loss of retromer results in increased levels of EV cargo. Since retromer is required to maintain lysosomal hydrolase activity ( Arighi et al, 2004 ; Cui et al, 2019 ; Seaman et al, 1998 ), general lysosomal dysfunction in retromer mutants might lead to the accumulation and release of material that would otherwise be targeted for degradation ( Bécot et al, 2020 ). We tested this by examining the lysosomal marker Spinster (Spin; Dermaut et al, 2005 ; Sweeney and Davis, 2002 ).…”

Local regulation of extracellular vesicle traffic by the synaptic endocytic machinery

“…Finally, our results suggest new interpretations of neurological disease mechanism. Defects in EV and endosomal trafficking are linked to neurodegenerative diseases such as Alzheimer’s Disease (Becot et al, 2020; Song et al, 2020; Winckler et al, 2018). Aged neurons exhibit increased APP endocytosis, leading to endosomal dysfunction and synapse loss (Burrinha et al, 2021).…”

Alteration of Payload in Extracellular Vesicles by Crosstalk With Mesenchymal Stem Cells From Different Origin

“…7c). It has been reported that amyloid-beta A4 precursor proteinbinding family A member 2 (APBA2) is involved in synaptic transport and junction of neurons [35], but they are also involved in improving immunity and cell regeneration [36]. We hypothesized that the antiin ammatory effect of HMEECs was increased by the expression of miRNA-638 in H:BM-M and APBA2 could be expected to be a candidate connection protein (Fig.…”