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Adv."],"published-print":{"date-parts":[[2026,8,28]]},"abstract":"<jats:p>\n                    Neurons actively shape immune responses that maintain central nervous system integrity. We identify SPP1 (secreted phosphoprotein 1) as a neuron-derived signal that reprograms microglia into a neuroprotective, homeostatic state after injury and during neurodegeneration. In mouse models of glaucoma and optic nerve damage, neuronal SPP1 enhances microglial autophagy, debris clearance, and anti-inflammatory activity, preserving neuronal survival and visual function. SPP1 is elevated in neurons of human and primate glaucomatous retinas, where SPP1\n                    <jats:sup>+<\/jats:sup>\n                    cells show increased resilience. In Alzheimer\u2019s disease brain, neuronal SPP1 correlates with neuronal survival, while microglia around A\u03b2 plaques display defective autophagy. In human iPSC co-cultures, SPP1 enhances microglial A\u03b2 clearance and prevents neurodegeneration. 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