Deacidification of distal lysosomes by neuronal aging drives synapse loss

Abstract

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. HighlightsO_LIEnlarged endolysosomes accumulate close to synapses in aged neurons and aged brain C_LIO_LILate-endosomes accumulate with neuronal aging C_LIO_LIAged lysosomes are less acidic and degradative despite accumulating Cathepsin D C_LIO_LIIncreasing acidification of aged lysosomes improves synapses, while deacidification recapitulates age-dependent synapse loss C_LI SummaryWe identify the downregulation of the lysosome degradative activity via deacidification as a neuronal aging mechanism contributing to aging-dependent synapse loss. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=130 SRC="FIGDIR/small/511921v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@808d15org.highwire.dtl.DTLVardef@1ae620forg.highwire.dtl.DTLVardef@1a7df3dorg.highwire.dtl.DTLVardef@314fe1_HPS_FORMAT_FIGEXP M_FIG C_FIG