Endosomal dysfunction impacts extracellular vesicle release: Central role in Aβ pathology

•AD is the most common neurodegenerative disease and the major cause of dementia.•Extracellular vesicles seem to play an important role in Aβ processing and trafficking.•Dysfunctional endosomal and autophagic pathways impairs APP processing in AD.•Exosomes may exert either beneficial as detrimental actions in AD.•Exosomes could be also used as biomarkers in AD. Alzheimer’s Disease (AD) is characterized by progressive loss of cognitive abilities; senile plaques represent the major histopathological findings. Amyloid precursor protein (APP) processing machinery, and its product amyloid-beta (Aβ) peptide, have been found in extracellular vesicles (EVs), specifically exosomes, which allows for Aβ peptide aggregation and subsequent senile plaques deposition. We review the APP processing imbalance in EVs, autophagic and endosomal pathways in AD. Increased intraluminal vesicle (ILV) production and exosome release appear to counteract the endosomal dysfunction of APP processing; however, this process results in elevated amyloidogenic processing of APP and augmented senile plaque deposition. Several players related to APP processing and dysfunctional endosomal-lysosomal-exosomal (and other EVs) pathway are described, and the interconnected systems are discussed. The components Arc, p75, Rab11 and retromer complex emerge as candidates for key convergent mechanisms that lead to increased EVs loaded with APP machinery and Aβ levels, in atrophy and damage of basal forebrain cholinergic neurons in AD.