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. 2020 Dec 18;14:602508. doi: 10.3389/fnins.2020.602508

FIGURE 1.

FIGURE 1

Toll-like receptor 4 (TLR4) signaling in Alzheimer disease (AD). Following ligand binding, TLR4 activates downstream signaling pathways through myeloid differentiation primary response protein 88 (Myd88)-dependent and -independent pathways, leading to nuclear factor-κB (NF-κB) and interferon-β (IFN-β) activation. TLR4 activation enhances amyloid-beta (Aβ) phagocytosis by microglia. Scavenger receptors (SRs), cluster of differentiation (CD)14, and murine formyl peptide receptor 2 (mFPR2) are involved in this process. The two different pathways involved in Aβ uptake by microglia are MyD88–p38–SR and the MyD88-independent Cdc42/Rac pathway. TLR4 activation reduces CD36 expression, thereby inhibiting CD36-mediated phagocytosis of Aβ. Triggering receptor expressed on myeloid cells 2 (TREM2) negatively regulates TLR-induced inflammatory cytokine production. TREM2 regulates TLR4/phospholipase C γ2 (PLCγ2)-dependent inflammatory signaling. TREM2 interacts with apolipoprotein E (ApoE) to affect phagocytosis of apoptotic neurons. High-mobility group box protein 1 (HMGB1) interacts with Aβ and inhibits Aβ phagocytosis by microglia via TLR4 signaling. Straight and dotted arrows represent activation and inhibition, respectively.