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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.


Related in: MedlinePlus

Lipopolysaccharide (LPS)‐ and oAβ‐induced tumor necrosis factor α (TNFα) secretion is higher with apolipoprotein E (apoE)4 than apoE3 and is blocked by toll‐like receptor (TLR)4 antagonism and p38α inhibition. Mixed glial cultures isolated from APOE‐TR and APOE‐knock‐out (KO) mice were incubated with (a) LPS (100 ng/mL), or (b) oAβ (10 μM) +/− LPS‐RS (10 μg/mL) for 24 h, and TNFα levels were measured in the media by ELISA. *p < 0.05. (c) Mixed glial cultures isolated from APOE4‐TR mice were incubated with oAβ (10 μM) and LPS‐RS, IAXO101, IAXO103, or controls (vehicle, IAXO202) for 24 h, and TNFα was measured in the media by ELISA. *p < 0.05 versus vehicle, #p < 0.05 versus LPS‐RS. Mixed glial cultures isolated from APOE3‐TR and APOE4‐TR mice were incubated with MW181, a p38α inhibitor, at the indicated concentrations for 30 min, followed by (d) LPS (100 ng/mL), or (e) oAβ (10 μM) for 24 h, and TNFα levels were measured in the media. Data are expressed as % vehicle control for each APOE genotype. *p < 0.05 versus vehicle for APOE3, #p < 0.05 versus vehicle for APOE4. n = 5–9.
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jnc13072-fig-0003: Lipopolysaccharide (LPS)‐ and oAβ‐induced tumor necrosis factor α (TNFα) secretion is higher with apolipoprotein E (apoE)4 than apoE3 and is blocked by toll‐like receptor (TLR)4 antagonism and p38α inhibition. Mixed glial cultures isolated from APOE‐TR and APOE‐knock‐out (KO) mice were incubated with (a) LPS (100 ng/mL), or (b) oAβ (10 μM) +/− LPS‐RS (10 μg/mL) for 24 h, and TNFα levels were measured in the media by ELISA. *p < 0.05. (c) Mixed glial cultures isolated from APOE4‐TR mice were incubated with oAβ (10 μM) and LPS‐RS, IAXO101, IAXO103, or controls (vehicle, IAXO202) for 24 h, and TNFα was measured in the media by ELISA. *p < 0.05 versus vehicle, #p < 0.05 versus LPS‐RS. Mixed glial cultures isolated from APOE3‐TR and APOE4‐TR mice were incubated with MW181, a p38α inhibitor, at the indicated concentrations for 30 min, followed by (d) LPS (100 ng/mL), or (e) oAβ (10 μM) for 24 h, and TNFα levels were measured in the media. Data are expressed as % vehicle control for each APOE genotype. *p < 0.05 versus vehicle for APOE3, #p < 0.05 versus vehicle for APOE4. n = 5–9.

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
Lipopolysaccharide (LPS)‐ and oAβ‐induced tumor necrosis factor α (TNFα) secretion is higher with apolipoprotein E (apoE)4 than apoE3 and is blocked by toll‐like receptor (TLR)4 antagonism and p38α inhibition. Mixed glial cultures isolated from APOE‐TR and APOE‐knock‐out (KO) mice were incubated with (a) LPS (100 ng/mL), or (b) oAβ (10 μM) +/− LPS‐RS (10 μg/mL) for 24 h, and TNFα levels were measured in the media by ELISA. *p < 0.05. (c) Mixed glial cultures isolated from APOE4‐TR mice were incubated with oAβ (10 μM) and LPS‐RS, IAXO101, IAXO103, or controls (vehicle, IAXO202) for 24 h, and TNFα was measured in the media by ELISA. *p < 0.05 versus vehicle, #p < 0.05 versus LPS‐RS. Mixed glial cultures isolated from APOE3‐TR and APOE4‐TR mice were incubated with MW181, a p38α inhibitor, at the indicated concentrations for 30 min, followed by (d) LPS (100 ng/mL), or (e) oAβ (10 μM) for 24 h, and TNFα levels were measured in the media. Data are expressed as % vehicle control for each APOE genotype. *p < 0.05 versus vehicle for APOE3, #p < 0.05 versus vehicle for APOE4. n = 5–9.
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jnc13072-fig-0003: Lipopolysaccharide (LPS)‐ and oAβ‐induced tumor necrosis factor α (TNFα) secretion is higher with apolipoprotein E (apoE)4 than apoE3 and is blocked by toll‐like receptor (TLR)4 antagonism and p38α inhibition. Mixed glial cultures isolated from APOE‐TR and APOE‐knock‐out (KO) mice were incubated with (a) LPS (100 ng/mL), or (b) oAβ (10 μM) +/− LPS‐RS (10 μg/mL) for 24 h, and TNFα levels were measured in the media by ELISA. *p < 0.05. (c) Mixed glial cultures isolated from APOE4‐TR mice were incubated with oAβ (10 μM) and LPS‐RS, IAXO101, IAXO103, or controls (vehicle, IAXO202) for 24 h, and TNFα was measured in the media by ELISA. *p < 0.05 versus vehicle, #p < 0.05 versus LPS‐RS. Mixed glial cultures isolated from APOE3‐TR and APOE4‐TR mice were incubated with MW181, a p38α inhibitor, at the indicated concentrations for 30 min, followed by (d) LPS (100 ng/mL), or (e) oAβ (10 μM) for 24 h, and TNFα levels were measured in the media. Data are expressed as % vehicle control for each APOE genotype. *p < 0.05 versus vehicle for APOE3, #p < 0.05 versus vehicle for APOE4. n = 5–9.
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&#8208;&beta; peptide (A&beta;) contribute to Alzheimer's disease (AD) pathology. APOE4 is the greatest AD&#8208;genetic risk factor; increasing risk up to 12&#8208;fold compared to APOE3, with APOE4&#8208;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 A&beta;&#8208;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&#8208;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 A&beta;&#8208;independent neuroinflammation, data for APOE&#8208;modulated A&beta;&#8208;induced neuroinflammation are surprisingly limited. We present data supporting the hypothesis that impaired apoE4 function modulates A&beta;&#8208;induced effects on inflammatory receptor signaling, including amplification of detrimental (toll&#8208;like receptor 4&#8208;p38&alpha;) and suppression of beneficial (IL&#8208;4R&#8208;nuclear receptor) pathways. To ultimately develop APOE genotype&#8208;specific therapeutics, it is critical that future studies define the dynamic NIP profile and pathways that underlie APOE&#8208;modulated chronic neuroinflammation.In this editorial review, we present data supporting the hypothesis that impaired apoE4 function modulates A&beta;&#8208;induced effects on inflammatory receptor signaling, including amplification of detrimental (TLR4&#8208;p38&alpha;) and suppression of beneficial (IL&#8208;4R&#8208;nuclear receptor) pathways, resulting in an adverse NIP that causes neuronal dysfunction. NIP, Neuroinflammatory phenotype; P.I., pro&#8208;inflammatory; A.I., anti&#8208;inflammatory.

No MeSH data available.


Related in: MedlinePlus