RT Journal Article SR Electronic T1 Increased exosome secretion in neurons aging in vitro by NPC1-mediated endosomal cholesterol buildup JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202101055 DO 10.26508/lsa.202101055 VO 4 IS 8 A1 Francesc X Guix A1 Ana Marrero Capitán A1 Álvaro Casadomé-Perales A1 Irene Palomares-Pérez A1 Inés López del Castillo A1 Verónica Miguel A1 Leigh Goedeke A1 Mauricio G Martín A1 Santiago Lamas A1 Héctor Peinado A1 Carlos Fernández-Hernando A1 Carlos G Dotti YR 2021 UL https://www.life-science-alliance.org/content/4/8/e202101055.abstract AB As neurons age, they show a decrease in their ability to degrade proteins and membranes. Because undegraded material is a source of toxic products, defects in degradation are associated with reduced cell function and survival. However, there are very few dead neurons in the aging brain, suggesting the action of compensatory mechanisms. We show in this work that ageing neurons in culture show large multivesicular bodies (MVBs) filled with intralumenal vesicles (ILVs) and secrete more small extracellular vesicles than younger neurons. We also show that the high number of ILVs is the consequence of the accumulation of cholesterol in MVBs, which in turn is due to decreased levels of the cholesterol extruding protein NPC1. NPC1 down-regulation is the consequence of a combination of upregulation of the NPC1 repressor microRNA 33, and increased degradation, due to Akt-mTOR targeting of NPC1 to the phagosome. Although releasing more exosomes can be beneficial to old neurons, other cells, neighbouring and distant, can be negatively affected by the waste material they contain.