title: APOE-modulated Aβ-induced neuroinflammation in Alzheimer's disease: current landscape, novel data, and future perspective.
abstract: 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. In this editorial review, we present data supporting the hypothesis that impaired apoE4 function modulates Aβ-induced effects on inflammatory receptor signaling, including amplification of detrimental (TLR4-p38α) and suppression of beneficial (IL-4R-nuclear receptor) pathways, resulting in an adverse NIP that causes neuronal dysfunction. NIP, Neuroinflammatory phenotype; P.I., pro-inflammatory; A.I., anti-inflammatory.
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois, Chicago, Illinois, USA.
authors.forename: Leon M
authors.initials: LM
authors.lastname: Tai
authors.forename: Shivesh
authors.initials: S
authors.lastname: Ghura
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Koster
authors.forename: Vaiva
authors.initials: V
authors.lastname: Liakaite
authors.forename: Mark
authors.initials: M
authors.lastname: Maienschein-Cline
authors.forename: Pinal
authors.initials: P
authors.lastname: Kanabar
authors.forename: Nicole
authors.initials: N
authors.lastname: Collins
authors.forename: Manel
authors.initials: M
authors.lastname: Ben-Aissa
authors.forename: Arden Zhengdeng
authors.initials: AZ
authors.lastname: Lei
authors.forename: Neil
authors.initials: N
authors.lastname: Bahroos
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Green
authors.forename: Bill
authors.initials: B
authors.lastname: Hendrickson
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Van Eldik
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: LaDu
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E
keywords: Alzheimer's disease; amyloid-β; apolipoprotein E; interleukin-4 receptor; neuroinflammation; toll-like receptor 4