Deacidification of endolysosomes by neuronal aging drives synapse loss

• Published in: Traffic (Copenhagen, Denmark) Denmark), 2023-08, Vol.24 (8), p.334-354
• Main Authors: Burrinha, Tatiana, Cunha, César, Hall, Michael J., Lopes‐da‐Silva, Mafalda, Seabra, Miguel C., Guimas Almeida, Cláudia
• Format: Article
• Language: English
• Subjects: Acidification; Adenosine Triphosphatases - metabolism; Aging; Axons; Cell body; Deacidification; endolysosomal system; Endosomes; Endosomes - metabolism; lysosome; Lysosomes; Lysosomes - metabolism; neuron; Neurons - metabolism; Organelles; Synapses
• ISSN: 1398-9219; 1600-0854
• DOI: 10.1111/tra.12889

Previously, we found that age‐dependent accumulation of beta‐amyloid is not sufficient to cause synaptic decline. Late‐endocytic organelles (LEOs) may be driving synaptic decline as lysosomes (Lys) are a target of cellular aging and relevant for synapses. We found that LAMP1‐positive LEOs increased in size and number and accumulated near synapses in aged neurons and brains. LEOs' distal accumulation might relate to the increased anterograde movement in aged neurons. Dissecting the LEOs, we found that late‐endosomes accumulated while there are fewer terminal Lys in aged neurites, but not in the cell body. The most abundant LEOs were degradative Lys or endolysosomes (ELys), especially in neurites. ELys activity was reduced because of acidification defects, supported by the reduction in v‐ATPase subunit V0a1 with aging. Increasing the acidification of aged ELys recovered degradation and reverted synaptic decline, while alkalinization or v‐ATPase inhibition, mimicked age‐dependent Lys and synapse dysfunction. We identify ELys deacidification as a neuronal mechanism of age‐dependent synapse loss. Our findings suggest that future therapeutic strategies to address endolysosomal defects might be able to delay age‐related synaptic decline. Enlarged late‐endocytic organelles accumulate close to synapses in aged neurons and the aged brain.Functionally, aged endolysosomes are less acidic and degradative despite accumulating cathepsin D. Increasing acidification of aged lysosomes improves synapses.Inversely, deacidification of mature neurons recapitulates lysosome dysfunction and age‐dependent loss of synapses.Thus, we identify the downregulation of the endolysosome degradative activity via deacidification as a neuronal aging mechanism contributing to synapse loss.