Interleukin (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.
Objective
We sought to determine the cell types responsible for IL-15 secretion in AD and their spatial relationship with amyloid-β (Aβ) pathology.
Methods
We performed immunofluorescent labeling of human postmortem frontal cortex tissue from cognitively intact and dementia patients and used RNA-sequencing and in vitro 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.
Results
In the prefrontal cortex of AD patients, we observed increased IL-15 colocalization with GFAP+ astrocytes (p = 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 in vitro (p = 0.0003 and p < 0.0001, respectively). We also show that neurons express increased IL2Rγ and IL2Rβ colocalization as Braak score increases (p = 0.0002) and that IL-15 is increased in the 5xFAD hippocampus compared to control animals (p = 0.0021).
Conclusions
Astrocytes 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.
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