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Funding Information: The authors thank the lab members for technical assistance, helpful discussions and for the critical reading of the manuscript. The authors thank Dr. S. Miserey‐Lenkei (Institute Curie), Dr. D. Barral, Dr. O. Vieira and Dr. S. Tenreiro (NOVA Medical School), for the gift of antibodies and reagents. The authors thank Dr. A. Marques, Dr. C. Escrevente, Dr. C. Perdigão and Dr. L. Lopes for helpful discussions. The authors thank L. Almeida for excel macros. The authors thank Dr. D. Barral (NOVA Medical School) and Dr. O. Vieira (NOVA Medical School) for the critical reading of the manuscript. The authors thank Dr. A. Farinho (NOVA Medical School Histology Facility), Dr. S. Marques (NOVA Medical School Animal Facility), Dr. T. Pereira (NOVA Medical School Microscopy Platform) and the Electron Microscopy Facility (Instituto Gulbenkian de Ciência). This project has received funding from the Marie Curie Integration Grant (PCIG‐GA‐2012‐334366‐trafficinAD; Marie Curie Actions, EC); iNOVA4Health—UID/Multi/04462/2019, a program financially supported by Fundação para a Ciência e Tecnologia (FCT)/Ministério da Educação e Ciência, through national funds and cofunded by FEDER under the PT2020 Partnership Agreement; Maratona da Saúde 2016; Investigator FCT (IF/00998/2012, FCT); CEECIND/00410/2017 financed by FCT; ALZ AARG‐19‐618007 Alzheimer's Association; from the research infrastructure PPBI‐POCI‐01‐0145‐FEDER‐022122, co‐financed by FCT (Portugal) and Lisboa2020, under the PORTUGAL2020 agreement (European Regional Development Fund); the European Union's Horizon 2020 Research and Innovation Program under Grant agreement no. 811087 (Lysocil). TB has been the recipient of an FCT doctoral fellowship (SFRH/BD/131513/2017). MLS was funded by FCT‐CEECIND/01536/2018. Publisher Copyright: © 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. 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. publishersversion epub_ahead_of_print |
