Interleukin‐3 is associated with soluble TREM2 and mediates amyloid and tau pathology in Alzheimer’s disease

Abstract

AbstractBackgroundDysfunction of glial cell communication is involved in Alzheimer’s disease (AD) pathogenesis. Recent studies reported that interleukin‐3 (IL‐3) participated in astrocyte‐microglia crosstalk and restricted pathological progression in AD mice. However, how IL‐3 relates to microglial activity and AD pathology in humans remains unclear.MethodWe included 311 participants with cerebrospinal fluid (CSF) IL‐3, sTREM2 (microglial biomarker), and AD biomarkers (Aβ42, p‐tau, and t‐tau) from the Alzheimer’s disease Neuroimaging Initiative (ADNI). We compared IL‐3 levels in different stages of AD and assessed the associations between IL‐3 with sTREM2 and AD biomarkers at baseline and with longitudinal cognitive change. Mediation models were used to explore the potential mechanism of how IL‐3 affects sTREM2 and AD pathology.ResultCSF IL‐3 levels decreased with increasing Aβ pathology and increased with increasing tau pathology, especially in cognitive impairment participants (Figure 1). CSF IL‐3 was significantly associated with CSF sTREM2 and CSF AD biomarkers (Figure 2). Mediation analysis showed that IL‐3 and sTREM2 mediated the effects of CSF Aβ on CSF tau pathology (βp‐tau = 0.053, βt‐tau = 0.055, all p < 0.001) (Figure 3).ConclusionOur findings suggest that IL‐3 is associated with the microglia biomarker and that they respond strongly to amyloid and tau pathologies. Hence, IL‐3 could be a key marker for clinical trial design. We encourage future studies on enhancing IL‐3 levels as a therapeutic intervention to slow the development of AD pathology.