Previously, we found that age-dependent beta-amyloid accumulation is not enough to cause synaptic decline. Here, we characterized endolysosomes (late-endosomes and lysosomes) in aged neurons and the aged brain, which might drive synaptic decline since lysosomes are a cellular aging target and relevant for synapses. Neuronal aging induces enlarged endolysosome accumulation in the aged neurons and brain, especially distally, related to the increased anterograde movement. Aged lysosomes abound in neurites but are less degradative due to deacidification despite cathepsin D buildup, leading to late-endosome accumulation. Increasing the acidification of aged lysosomes by ML-SA1 treatment increased degradation and reverted synaptic decline, while lysosome alkalinization by chloroquine treatment mimicked age-dependent lysosome dysfunction and synaptic decline. We identify the deacidification of distal lysosomes as a neuronal mechanism of age-dependent synapse loss. Our findings suggest that future therapeutic strategies to address lysosomal defects might be able to delay age-related synaptic decline.

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.

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