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TLR4‐p38 pathway as a mechanism of APOE‐modulated neuroinflammation in Alzheimer disease (1056.6)
Author(s) -
LaDu Mary,
Wohlgenant Susan,
Van Eldik Linda,
Tai Leon
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1056.6
Subject(s) - neuroinflammation , apolipoprotein e , tlr4 , proinflammatory cytokine , microglia , inflammation , tumor necrosis factor alpha , neurotoxicity , p38 mitogen activated protein kinases , signal transduction , immunology , medicine , biology , pharmacology , microbiology and biotechnology , disease , toxicity , mapk/erk pathway
Soluble oligomeric Aβ (oAβ) is a neurotoxic aggregate thought to be a proximal cause of Alzheimer disease (AD). Chronic inflammation of glial cells induced by oAβ‐induced likely results in both direct neurotoxicity and decreased phagocytic clearance of Aβ and cellular debris. The strongest genetic risk factor for AD is the ε4 allele of the APOE gene. As APOE4 is associated with a proinflammatory response compared to APOE3, we determined the APOE‐specific neuroinflammatory phenotype in novel EFAD transgenic mice, which overexpress human Aβ42 and apolipoprotein E (apoE). Overall, our data are consistent with an increased pro‐inflammatory, anti‐phagocytic (M1) and reduced anti‐inflammatory, repair, (M2) response in E4FAD compared to E3FAD mice. To determine the mechanism underlying these effects and test our hypothesis that TLR4 signaling mediates Aβ‐induced APOE‐modulated neuroinflammation, a primary glial screen was developed. LPS‐ and oAβ‐induced secretion of TNF‐α is concentration dependent and higher with apoE4 than apoE3 in vitro. Importantly, TLR4 antagonists (LPS‐RS, IAXO series), and an inhibitor of p38α (a down‐stream target of TLR4) prevented oAβ42‐induced TNF‐α secretion. Thus, TLR4 signaling represents a novel pathway for APOE4‐specific neuroinflammation.