Rommelaere, S.; Wang, S.; Vernon, S.; Krakovic, K.; Boquete, J. P.; McCabe, B. D.; Lemaitre, B.

Inflammation increases with aging and contributes to neurodegeneration, yet the principles that determine how immune effectors target host neural tissue remain poorly understood. Antimicrobial peptides (AMPs) are central components of innate immune defenses strongly induced upon infection and upon aging. Studies have shown that AMPs can exhibit cytotoxicity toward host cells, pointing to a role in neurodegeneration. We show that cationic AMPs selectively bind and damage motoneurons that expose phosphatidylserine (PS), an anionic phospholipid normally restricted to the inner leaflet of the plasma membrane. Both infection and aging increase neuronal PS exposure alongside AMP expression. AMP binding occurs in a PS-dependent manner, leading to synaptic bouton fragmentation, accelerated neuronal aging, and locomotor decline. This toxicity is prevented in Drosophila by Turandot proteins, which reduce AMP-PS interactions on motoneurons. Together, our findings define a molecular mechanism underlying neuronal susceptibility to immunopathology and a set of proteins with neuroprotective potential.