TY - JOUR
T1 - APOE-modulated Aβ-induced neuroinflammation in Alzheimer's disease
T2 - Current landscape, novel data, and future perspective
AU - Tai, Leon M.
AU - Ghura, Shivesh
AU - Koster, Kevin P.
AU - Liakaite, Vaiva
AU - Maienschein-Cline, Mark
AU - Kanabar, Pinal
AU - Collins, Nicole
AU - Ben-Aissa, Manel
AU - Lei, Arden Zhengdeng
AU - Bahroos, Neil
AU - Green, Stefan J.
AU - Hendrickson, Bill
AU - Van Eldik, Linda J.
AU - LaDu, Mary Jo
N1 - Publisher Copyright:
© 2015 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of The International Society for Neurochemistry.
PY - 2015/3/18
Y1 - 2015/3/18
N2 - Chronic glial activation and neuroinflammation induced by the amyloid-β peptide (Aβ) contribute to Alzheimer's disease (AD) pathology. APOE4 is the greatest AD-genetic risk factor; increasing risk up to 12-fold compared to APOE3, with APOE4-specific neuroinflammation an important component of this risk. This editorial review discusses the role of APOE in inflammation and AD, via a literature review, presentation of novel data on Aβ-induced neuroinflammation, and discussion of future research directions. The complexity of chronic neuroinflammation, including multiple detrimental and beneficial effects occurring in a temporal and cell-specific manner, has resulted in conflicting functional data for virtually every inflammatory mediator. Defining a neuroinflammatory phenotype (NIP) is one way to address this issue, focusing on profiling the changes in inflammatory mediator expression during disease progression. Although many studies have shown that APOE4 induces a detrimental NIP in peripheral inflammation and Aβ-independent neuroinflammation, data for APOE-modulated Aβ-induced neuroinflammation are surprisingly limited. We present data supporting the hypothesis that impaired apoE4 function modulates Aβ-induced effects on inflammatory receptor signaling, including amplification of detrimental (toll-like receptor 4-p38α) and suppression of beneficial (IL-4R-nuclear receptor) pathways. To ultimately develop APOE genotype-specific therapeutics, it is critical that future studies define the dynamic NIP profile and pathways that underlie APOE-modulated chronic neuroinflammation.
AB - Chronic glial activation and neuroinflammation induced by the amyloid-β peptide (Aβ) contribute to Alzheimer's disease (AD) pathology. APOE4 is the greatest AD-genetic risk factor; increasing risk up to 12-fold compared to APOE3, with APOE4-specific neuroinflammation an important component of this risk. This editorial review discusses the role of APOE in inflammation and AD, via a literature review, presentation of novel data on Aβ-induced neuroinflammation, and discussion of future research directions. The complexity of chronic neuroinflammation, including multiple detrimental and beneficial effects occurring in a temporal and cell-specific manner, has resulted in conflicting functional data for virtually every inflammatory mediator. Defining a neuroinflammatory phenotype (NIP) is one way to address this issue, focusing on profiling the changes in inflammatory mediator expression during disease progression. Although many studies have shown that APOE4 induces a detrimental NIP in peripheral inflammation and Aβ-independent neuroinflammation, data for APOE-modulated Aβ-induced neuroinflammation are surprisingly limited. We present data supporting the hypothesis that impaired apoE4 function modulates Aβ-induced effects on inflammatory receptor signaling, including amplification of detrimental (toll-like receptor 4-p38α) and suppression of beneficial (IL-4R-nuclear receptor) pathways. To ultimately develop APOE genotype-specific therapeutics, it is critical that future studies define the dynamic NIP profile and pathways that underlie APOE-modulated chronic neuroinflammation.
KW - Alzheimer's disease
KW - amyloid-β
KW - apolipoprotein E
KW - interleukin-4 receptor
KW - neuroinflammation
KW - toll-like receptor 4
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U2 - 10.1111/jnc.13072
DO - 10.1111/jnc.13072
M3 - Review article
C2 - 25689586
AN - SCOPUS:84927594690
SN - 0022-3042
VL - 133
SP - 465
EP - 488
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 4
ER -