Enhancing Tyro3 signalling ameliorates IL-1β production through STAT1 in Alzheimer's disease models.

Neuroinflammation plays a vital role in determining the trajectory of Alzheimer's disease (AD) progression. In AD brain, microglial exposure to pathological amyloid β (Aβ42) and tau peptide aggregates results in an NLRP3 inflammasome-activated pro-inflammatory response that ranges from mild to severe. Recently we have shown that dementia subjects with higher levels of soluble TAM receptors Tyro3 and AXL in the cerebrospinal fluid (CSF) indicated cognitive protection. The molecular mechanism for this protective effect of TAM receptors is unknown. Here, we identified a beneficial role of TAM receptors using Tyro3-overexpressing (Tyro3OE) and Axl-overexpressing (AxlOE) THP-1 cells. In the Tyro3OE cells, the levels of the pro-inflammatory cytokine IL-1β were markedly decreased in the AD microenvironment (tau + Aβ42) and the classical NLRP3 inflammasome model (LPS + Nigericin) in comparison to the control cells. This was mediated by increased STAT1 phosphorylation and reduced IL-1β transcription enhancer C-EBP- β in Tyro3OE cells. The use of the JAK1/2 inhibitor Ruxolitinib reduced the phosphorylation of STAT1, leading to a partial restoration of IL-1β in the Tyro3OE cells. Lastly, we found a significantly reduced IL-1β in the brains of AD mice that has activated TAM signalling through Gas6-α-Aβ lentiviral injection. In summary, TAM receptor Tyro3 overexpression decreased AD-associated IL-1β release from macrophages thereby uncovering a potential beneficial role for TAM receptors during neuroinflammation in AD.

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PMID: 41206011