Astrocytes upregulate interleukin-15 in response to neuroinflammation during Alzheimer's disease

BackgroundInterleukin (IL)-15 is a pleiotropic cytokine linked to cognition that is increased in the cerebrospinal fluid of Alzheimer's disease (AD) patients; however, the cellular source of IL-15 and IL-15-sensing cells in AD has not been described.ObjectiveWe sought to determine the cell types responsible for IL-15 secretion in AD and their spatial relationship with amyloid-β (Aβ) pathology.MethodsWe performed immunofluorescent labeling of human postmortem frontal cortex tissue from cognitively intact and dementia patients and used RNA-sequencing and <i>in vitro</i> assays to confirm the stimulus and source of IL-15. We also assessed the hippocampus of 6-7-month-old 5xFAD mice for cytokine levels using multiplex ELISA.ResultsIn the prefrontal cortex of AD patients, we observed increased IL-15 colocalization with GFAP⁺ astrocytes (<i>p</i> = 0.0181) near Aβ plaques and demonstrate that astrocytes, but not neurons, upregulate IL-15 in response to interferon-γ and tumor necrosis factor-α <i>in vitro</i> (<i>p</i> = 0.0003 and <i>p</i> < 0.0001, respectively). We also show that neurons express increased IL2Rγ and IL2Rβ colocalization as Braak score increases (<i>p</i> = 0.0002) and that IL-15 is increased in the 5xFAD hippocampus compared to control animals (<i>p</i> = 0.0021).ConclusionsAstrocytes are a source of IL-15 in AD, particularly near localized Aβ pathology, and neurons are poised to respond. The 5xFAD model recapitulates the hippocampal inflammatory milieu associated with AD and may be a useful tool to study the role of IL-15 in the context of Aβ pathology.