HARNESSING TYPE II INNATE LYMPHOID CELLS FOR NEUROPROTECTION AGAINST SYSTEMIC CHALLENGE IN ALZHEIMER’S DISEASE

Growing evidence highlights the importance of type II innate lymphoid cells (ILC2) in modulating the brain's response during systemic infection. However, the mechanisms by which these peripheral immune cells infiltrate the brain remain unclear. Here, 5xFAD Alzheimer’s disease mice and C57BL/6J strain-matched controls were subjected to a single intraperitoneal (i.p.) injection of LPS, and ILC2 populations were compared in various CNS fractions. We report that i.p. LPS leads to the aggregation of CD127⁺ ST2⁺ Gata3⁺ ILC2 specifically around the dura mater of the brain. Congruently, qPCR analysis revealed significantly upregulated mRNA expressions of IL-33, IL-25, and IL-13 in the dura mater and choroid plexus. Crucially, we observed a significant reduction in the population of ILC2s within the dura mater of 5xFAD mice following systemic inflammation. This was associated with significantly increased pathological amyloid (6E10) load in the hippocampus, suggesting that impairments in ILC2 recruitment in the dura mater directly contributes to AD pathogenesis. Based on these observations, we performed intracerebroventricular adoptive transfers of primary ILC2s in 5xFAD mice subjected to intraperitoneal LPS. To do so, IL-5 mCherry+ ST2+ ILC2s were extracted from naïve mice using FACS and cultured in vitro with serums of IL-33, IL-7, IL-2. Primary ILC2s were delivered to the cerebroventricular space. Preliminary results demonstrate successful increases in ST2+ ILC2 populations in the dura mater of 5xFAD decreased Iba1+ microglia in response to systemic challenge. These findings underscore the critical role of ILC2 in modulating the neuroinflammatory environment and potentially alleviate cognitive decline in Alzheimer's disease.