| Popis: |
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.HighlightsEnlarged endolysosomes accumulate close to synapses in aged neurons and aged brainLate-endosomes accumulate with neuronal agingAged lysosomes are less acidic and degradative despite accumulating Cathepsin DIncreasing acidification of aged lysosomes improves synapses, while deacidification recapitulates age-dependent synapse lossSummaryWe identify the downregulation of the lysosome degradative activity via deacidification as a neuronal aging mechanism contributing to aging-dependent synapse loss.Graphical abstract |
