Loss of the NF-κB negative regulator Pirk in <i>Drosophila</i> links brain and gut immunity to neurodegeneration

A gut-brain axis influenced by host innate immunity and resident microbiota has been implicated in neurological conditions including Alzheimer's disease. However, the precise connection of innate immunity to Alzheimer's disease remains unclear. Using Pirk, a negative regulator of the IMD/NF-κB pathway in <i>Drosophila</i>, we studied the neurological phenotypes induced when genetically predisposing flies to chronically over-active immunity. <i>Pirk</i> mutants exhibited age-dependent neurological phenotypes such as reduced locomotion and altered sleep patterns coupled to an increased number of brain lesions. Gut-specific <i>pirk-</i>RNA interference led to earlier onset of the neurological phenotypes which, alongside changes in intestinal bacteria in <i>pirk</i> mutants, highlighted a potential early role for the intestinal ecosystem in the onset of neurodegeneration. In contrast, glia-specific RNA interference of <i>pirk</i> resulted in late onset of the relevant phenotypes suggesting a later contribution of the nervous system to the underlying neuropathology. Knockout of the antimicrobial peptide (AMP) gene <i>AttacinD</i> or rearing flies in axenic conditions recovered some of the neurological phenotypes, suggesting both chronic AMP gene expression as well as gut bacteria changes as mediators. Our results indicate an evolutionarily conserved path to neurodegeneration linked to dysregulated immunity. They also reveal that in this context, age-dependent neurodegeneration can happen in less complex non-vertebrate brains in the absence of beta-amyloid or tau aggregation.