Abstract
Advanced age is the greatest risk factor for neurodegenerative disorders, but the mechanisms that render the senescent brain vulnerable to disease are unclear. Glial immune responses provide neuroprotection in a variety of contexts. Thus, we explored how glial responses to neurodegeneration are altered with age. Here we show that glia–axon phagocytic interactions change dramatically in the aged Drosophila brain. Aged glia clear degenerating axons slowly due to low phosphoinositide-3-kinase (PI3K) signalling and, subsequently, reduced expression of the conserved phagocytic receptor Draper/MEGF10. Importantly, boosting PI3K/Draper activity in aged glia significantly reverses slow phagocytic responses. Moreover, several hours post axotomy, early hallmarks of Wallerian degeneration (WD) are delayed in aged flies. We propose that slow clearance of degenerating axons is mechanistically twofold, resulting from deferred initiation of axonal WD and reduced PI3K/Draper-dependent glial phagocytic function. Interventions that boost glial engulfment activity, however, can substantially reverse delayed clearance of damaged neuronal debris.
Highlights
Advanced age is the greatest risk factor for neurodegenerative disorders, but the mechanisms that render the senescent brain vulnerable to disease are unclear
We demonstrate that glial clearance of damaged axons is significantly delayed in aged animals due to an age-dependent decline in translation of the critical glial recognition engulfment receptor Draper, which results from reduced phosphoinositide-3kinase (PI3K) signalling
We used an acute axotomy assay in the olfactory system of adult flies to explore how ageing influences glial responses to axon degeneration in vivo
Summary
Advanced age is the greatest risk factor for neurodegenerative disorders, but the mechanisms that render the senescent brain vulnerable to disease are unclear. Microglia and astrocytes often display enlarged soma and shorter projections as compared with their young counterparts[4,5,6,7] These age-dependent changes in morphology suggest that aged glia may be compromised in their ability to sense and/or respond to neuronal stress and degeneration and, in vitro studies have suggested that microglia harvested from older animals display defective phagocytic activity[8]. We demonstrate that glial clearance of damaged axons is significantly delayed in aged animals due to an age-dependent decline in translation of the critical glial recognition engulfment receptor Draper, which results from reduced phosphoinositide-3kinase (PI3K) signalling. In aged glia, Draper levels fall below a critical threshold required to activate a Draperdependent STAT92E transcriptional programme in local glia in response to axon injury
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