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Disclosing lysosomal dysfunction with neuronal aging
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ABSTRACT
Neuronal aging constitutes the greatest known risk factor for the pathological initiation of late-onset Alzheimer’s Disease. Despite lysosomal and synaptic dysfunction representing the earliest known potentiators of disease etiology, a significant knowledge gap regarding lysosomal dynamics in physiologically-relevant synaptically connected neurons still exists. We hypothesized that the age-related disruption of lysosomal homeostasis is a potentiator of early synaptic degeneration in AD. We aimed to understand the lysosomal-associated molecular changes underlying overall neuronal aging and locally at synapses. We characterized late endosomal and lysosomal (endolysosomal) distribution and molecular composition in several neuronal subcellular compartments and synapses using mouse primary hippocampal/cortical neurons aged in culture and hippocampal/cortical-derived synaptosomes, with the combined use of immunofluorescence, immunoblotting, genetic manipulation, and quantitative subcellular single-cell analysis techniques. We documented that endolysosomes are mainly distributed along the dendrites, but display a higher density in the soma of mature neurons. Comparatively, we found fewer endolysosomes in the dendrites and axons of aged neurons. We also noted that endolysosomes were distributed differently in the aged soma, accumulating in the axon hillock region. Moreover, endolysosomes were larger and more LAMP1 immunoreactive in aged neurons. When assessing the different subpopulations of endolysosomes, we found that the ratio of LAMP1+ late endosomes increased while the ratio of LAMP1+ degradative lysosomes remained unaltered in aged neurons. These aged LAMP1+ endolysosomes accumulated Aβ42, the most toxic Aβ peptide, particularly in dendrites and the soma. Further, we found endolysosomes pre- and postsynaptically in both in vitro primary neurons and in vivo mice hippocampal/cortical synaptosomes. In aged neurons, the synaptic endolysosomal association was reduced. Our data suggest that the endolysosomal intrinsic features and mapping differ significantly in synaptically connected mature neurons, changing considerably with neuronal aging. Moreover, we revealed a high degree of complexity surrounding the molecular dynamics driving early aging-dependent changes in the maturation of distinct LAMP1+ endolysosomal subpopulations. We argue that lysosomal acidification is the likely driver in a very complex lysosomal-centric synaptic regulation. Our evidence advocate that biomolecular changes in endolysosomal dynamics with neuronal aging might be at the core of a large and multi-layered cascade of synaptic dysfunction that may potentiate AD.
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Neuronal aging Alzheimer’s Disease Lysosomal homeostasis