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APOE ‐ modulated A β ‐ induced neuroinflammation in Alzheimer's disease: current landscape, novel data, and future perspective

View Article: PubMed Central - PubMed

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.

No MeSH data available.


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Proposed hypothesis of APOE‐modulated Aβ‐induced neuroinflammation. (a and b) Compared to APOE3, with APOE4: Lower lipoprotein lipidation and apolipoprotein E (apoE)4 levels result in lower apoE receptor signaling and levels, which with Aβ‐induction amplifies detrimental and suppresses beneficial inflammatory receptor signaling. This imbalance leads to an adverse neuroinflammatory phenotype (NIP) and downstream neuronal dysfunction. ApoE signaling via the apoE receptors may suppress Aβ‐induced activation of toll‐like receptor (TLR)4‐p38α signaling and potentiate IL‐4R signaling through pathways that converge on nuclear receptor signaling. PI, pro‐inflammatory; AI, anti‐inflammatory; Green, astrocyte; red, microglia.
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jnc13072-fig-0004: Proposed hypothesis of APOE‐modulated Aβ‐induced neuroinflammation. (a and b) Compared to APOE3, with APOE4: Lower lipoprotein lipidation and apolipoprotein E (apoE)4 levels result in lower apoE receptor signaling and levels, which with Aβ‐induction amplifies detrimental and suppresses beneficial inflammatory receptor signaling. This imbalance leads to an adverse neuroinflammatory phenotype (NIP) and downstream neuronal dysfunction. ApoE signaling via the apoE receptors may suppress Aβ‐induced activation of toll‐like receptor (TLR)4‐p38α signaling and potentiate IL‐4R signaling through pathways that converge on nuclear receptor signaling. PI, pro‐inflammatory; AI, anti‐inflammatory; Green, astrocyte; red, microglia.

Mentions: This review discusses the role of APOE in inflammation and Alzheimer's disease (AD), via a literature review (Fig. 1), presentation of novel data on APOE‐modulated Aβ‐induced neuroinflammation (Figs 2 and 3), and discussion of future research directions (Fig. 4).


APOE ‐ modulated A β ‐ induced neuroinflammation in Alzheimer's disease: current landscape, novel data, and future perspective
Proposed hypothesis of APOE‐modulated Aβ‐induced neuroinflammation. (a and b) Compared to APOE3, with APOE4: Lower lipoprotein lipidation and apolipoprotein E (apoE)4 levels result in lower apoE receptor signaling and levels, which with Aβ‐induction amplifies detrimental and suppresses beneficial inflammatory receptor signaling. This imbalance leads to an adverse neuroinflammatory phenotype (NIP) and downstream neuronal dysfunction. ApoE signaling via the apoE receptors may suppress Aβ‐induced activation of toll‐like receptor (TLR)4‐p38α signaling and potentiate IL‐4R signaling through pathways that converge on nuclear receptor signaling. PI, pro‐inflammatory; AI, anti‐inflammatory; Green, astrocyte; red, microglia.
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC4400246&req=5

jnc13072-fig-0004: Proposed hypothesis of APOE‐modulated Aβ‐induced neuroinflammation. (a and b) Compared to APOE3, with APOE4: Lower lipoprotein lipidation and apolipoprotein E (apoE)4 levels result in lower apoE receptor signaling and levels, which with Aβ‐induction amplifies detrimental and suppresses beneficial inflammatory receptor signaling. This imbalance leads to an adverse neuroinflammatory phenotype (NIP) and downstream neuronal dysfunction. ApoE signaling via the apoE receptors may suppress Aβ‐induced activation of toll‐like receptor (TLR)4‐p38α signaling and potentiate IL‐4R signaling through pathways that converge on nuclear receptor signaling. PI, pro‐inflammatory; AI, anti‐inflammatory; Green, astrocyte; red, microglia.
Mentions: This review discusses the role of APOE in inflammation and Alzheimer's disease (AD), via a literature review (Fig. 1), presentation of novel data on APOE‐modulated Aβ‐induced neuroinflammation (Figs 2 and 3), and discussion of future research directions (Fig. 4).

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus