Jungers Center for Neurosciences Research, Department of Neurology, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97239, USA.
Nat Commun. 2016 Sep 20;7:12871. doi: 10.1038/ncomms12871.
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.
年龄增长是神经退行性疾病的最大风险因素，但导致衰老大脑易患疾病的机制尚不清楚。神经胶质的免疫反应在多种情况下提供神经保护。因此，我们探讨了神经退行性变过程中神经胶质反应如何随年龄而变化。在这里，我们表明，衰老果蝇大脑中的神经胶质-轴突吞噬相互作用发生了巨大变化。由于磷酸肌醇 3-激酶（PI3K）信号降低，以及保守的吞噬受体 Draper/MEGF10 的表达减少，衰老的神经胶质清除变性轴突的速度非常缓慢。重要的是，在衰老的神经胶质中增强 PI3K/Draper 活性可显著逆转缓慢的吞噬反应。此外，在轴突切断后几个小时，衰老果蝇中 Wallerian 变性（WD）的早期标志被延迟。我们提出，变性轴突的清除缓慢在机制上是双重的，这是由于轴突 WD 的启动延迟和 PI3K/Draper 依赖性神经胶质吞噬功能降低所致。然而，增强神经胶质吞噬活性的干预措施可以大大逆转受损神经元碎片的清除延迟。
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