Microglial TLR4-Lyn kinase is a critical regulator of neuroinflammation, Aβ phagocytosis, neuronal damage, and cell survival in Alzheimer’s disease

Apr 2, 2025Scientific reports

Microglial TLR4-Lyn kinase controls brain inflammation, amyloid removal, nerve cell damage, and survival in Alzheimer's disease

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Abstract

An increased direct protein-protein interaction between and was observed in the brains of 5XFAD mice compared to wild-type mice.

The interaction between TLR4 and Lyn kinase may influence inflammatory and phagocytosis signaling pathways in Alzheimer's disease.
In the absence of Lyn, 5XFAD x Lyn mice showed increased expression of protective Syk kinase and enhanced Aβ phagocytosis.
Increased astrocyte activity and decreased neuronal dystrophy were noted in 5XFAD x Lyn mice.
in 5XFAD mice exhibited higher levels of TLR4 and Lyn, along with greater inflammatory cytokine production.
In vitro treatment with TLR4-Lyn Interaction Modulators (TLIMs) resulted in increased Aβ phagocytosis and decreased neuronal dystrophy.

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(DAM) are a focus in Alzheimer's disease (AD) research due to their central involvement in the response to amyloid-beta plaques. Microglial Toll-like receptor 4 () is instrumental in the binding of fibrillary amyloid proteins, while (Lyn) is a member of the Src family of non-receptor tyrosine kinases involved in immune signaling. Lyn is a novel, non-canonical, intracellular adaptor with diverse roles in cell-specific signaling which directly binds to TLR4 to modify its function. Lyn can be activated in response to TLR4 stimulation, leading to phosphorylation of various substrates and modulation of inflammatory and phagocytosis signaling pathways. Here, we investigated the TLR4-Lyn interaction in neuroinflammation using WT, 5XFAD, and 5XFAD x Lynmouse models by western blotting (WB), co-immunoprecipitation (co-IP), immunohistochemistry (IHC) and flow cytometric (FC) analysis. A spatial transcriptomic analysis of microglia in WT, 5XFAD, and 5XFAD x Lynmice revealed essential genes involved in neuroinflammation, Aβ phagocytosis, and neuronal damage. Finally, we explored the effects of a synthetic, TLR4-Lyn modulator protein (TLIM) through an in vitro AD model using primary murine microglia. Our WB, co-IP, IHC, and FC data show an increased, novel, direct protein-protein interaction between TLR4 and Lyn kinase in the brains of 5XFAD mice compared to WT. Furthermore, in the absence of Lyn (5XFAD x Lynmice); increased expression of protective Syk kinase was observed, enhanced microglial Aβ phagocytosis, increased astrocyte activity, decreased neuronal dystrophy, and a further increase in the cell survival signaling and protective DAM population was noted. The DAM population in 5XFAD mice which produce more inflammatory cytokines and phagocytose more Aβ were observed to express greater levels of TLR4 and Lyn. Pathway analysis comparison between WT, 5XFAD, and 5XFAD x Lynmice supported these findings via our microglial spatial transcriptomic analysis. Finally, we created an in vitro co-culture system with primary murine microglial and primary murine hippocampal cells exposed to Aβ as a model of AD. When these co-cultures were treated with our TLR4-Lyn Interaction Modulators (TLIMs), an increase in Aβ phagocytosis and a decrease in neuronal dystrophy was seen. Lyn kinase has a central role in modulating TLR4-induced inflammation and Syk-induced protection in a 5XFAD mouse model. Our TLIMs ameliorate AD sequalae in an in vitro model of AD and could be a promising therapeutic strategy to treat AD. -/--/--/--/-

Key numbers

1.5×

Increase in Population

Comparing populations in Lyn-deficient vs. control 5XFAD mice.

17.9 nM

TLIM IC50 Concentration

Determined through dose-response curve for TLIM treatment.

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Microglial TLR4-Lyn kinase is a critical regulator of neuroinflammation, Aβ phagocytosis, neuronal damage, and cell survival in Alzheimer’s disease

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