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• W2896838984 abstract "AD is pathologically hallmarked by deposition of amyloid-β (Aβ) peptides as β-amyloid plaques, formation of neurofibrillary tangles and low-level, chronic activation of brain innate immunity. The amyloid cascade hypothesis purports that Aβ accumulation resulting from an imbalance between Aβ production and clearance is the principle etiopathological event in AD. Toll-like receptors (TLRs) are one mechanism by which microglia recognize Aβ. However, despite presence of activated microglia in close vicinity of amyloid plaques in AD, these innate immune cells ultimately fail to remove plaques. IRAK-M is an inhibitor of TLR signaling that functions both by 1) inhibiting ‘classical NF-κB signaling’ and the transcription of pro-inflammatory genes and 2) activating ‘alternative NF-κB signaling’, which inhibits the classical NF-κB signaling pathway. We have previously shown that genetic removal of IRAK-M in APP/PS1 mice beneficially activates microglia to phagocytose Aβ, leading to reduced plaque burden and cognitive betterment. In the present work, we investigated the relative contributions of IRAK-M NF-κB signaling functions in AD. We evaluated TLR/IRAK/NF-κB signaling in post-mortem hippocampal lysates from AD patients and age-matched, non-demented controls as well as APP/PS1 IRAK-M sufficient and deficient mice. To assess the relative contributions of IRAK-M in the AD context, we stably introduced wild-type (WT) IRAK-M and mutant IRAK-M (lacking the functional N-terminal death domain region; IRAK-MΔDD) into human microglia prior to stimulation with Aβ1-42 microaggregates. IRAK-M expression was significantly increased in AD vs. control brains. A similar pattern of results was evident in APP/PS1 compared to wild-type mice. APP/PS1 mice demonstrated increases in multiple alternative NF-κB signaling molecules including IκBα, A20, and SOCS1 that were abolished in APP/PS1/IRAK-M−⁄− mice. Accordingly, alternative activation markers including MEKK3 were elevated in AD brains vs. controls. IRAK-MΔDD human microglia had significantly increased Aβ uptake associated with decreased IκBα, A20, and SOCS1 levels compared to WT IRAK-M cells. Collectively, these data suggest that IRAK-M contributes to microglial Aβ tolerance by increasing alternative NF-κB signaling. Inhibition of IRAK-M may represent a pharmacological target to enable cerebral innate immune Aβ phagocytosis and clearance." @default.
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• W2896838984 date "2018-07-01" @default.
• W2896838984 modified "2023-10-18" @default.
• W2896838984 title "P2‐200: IRAK‐M PROMOTES MICROGLIAL Aβ TOLERANCE BY ACTIVATING ALTERNATIVE NF‐KB SIGNALING" @default.
• W2896838984 doi "https://doi.org/10.1016/j.jalz.2018.06.887" @default.
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