Alzheimer's Risk Factors Age,  &lt;i&gt;APOE&lt;/i&gt; Genotype, and Sex Drive Distinct Molecular Pathways

Zhao, Na; Ren, Yingxue; Yu, Yun William; Qiao, Wenhui; Felton, Lindsey M.; MahmoudianDehkordi, Siamak; Kueider‐Paisley, Alexandra; Shue, Francis; Zheng, Jiaying; Attrebi, Olivia N.; Martens, Yuka A.; Li, Zonghua; Tachibana, Masaya; Aikawa, Tomonori; Oue, Hiroshi; Sonoustoun, Berkiye; Job, Lucy; Yamazaki, Akari; Liu, Chia-Chen; Asmann, Yan W.; Ertekin-Taner, Nilüfer; Kanekiyo, Takahisa; Kaddurah‐Daouk, Rima; Bu, Guojun

doi:10.2139/ssrn.3430711

Cited by 11 publications

(14 citation statements)

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“…It is plausible that astrocytes contribute to the greater LTB4, ROS, and iNOS production with APOE4. An extensive recent proteomic and lipidomic investigation in animal brains of ApoE-TR mice corroborates the enhanced eicosanoid signaling with APOE4 [49]. LTB4 signaling may have a prominent role in inducing oxidative stress.…”

Section: Both Human and Mouse Modelsmentioning

confidence: 68%

Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4

Solomon

Fonteh

et al. 2021

Preprint

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Background: Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and the risk of developing late-onset Alzheimer's disease (AD), but the mechanisms for this association are not clear. The activation of calcium-dependent cytosolic phospholipase A2 (cPLA2) is involved in inflammatory signaling and is elevated within the plaques of AD brains. The relation between APOE4 genotype and cPLA2 activity is not known.Methods: Mouse primary astrocytes, mouse and human brain samples differing by APOE genotypes were collected for measuring cPLA2 expression, phosphorylation, and activity in relation to measures of inflammation and oxidative stress. Results: Greater cPLA2 phosphorylation, cPLA2 activity and leukotriene B4 (LTB4) levels were identified in ApoE4 compared to ApoE3 in primary astrocytes, brains of ApoE-targeted replacement (ApoE-TR) mice, and in human brain homogenates from the inferior frontal cortex of patients with AD carrying APOE3/4 compared to APOE3/3. Greater cPLA2 phosphorylation was also observed in human postmortem frontal cortical synaptosomes and primary astrocytes after treatment with recombinant ApoE4 ex vivo. In ApoE4 astrocytes, the greater levels of LTB4, reactive oxygen species (ROS), and inducible nitric oxide synthase (iNOS) were reduced after cPLA2 inhibition. Conclusions: Our findings implicate greater activation of cPLA2 signaling system with APOE4, which could represent a potential drug target for mitigating the increased neuroinflammation with APOE4 and AD.

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Section: Both Human and Mouse Modelsmentioning

confidence: 68%

Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4

Solomon

Fonteh

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…It is plausible that astrocytes and microglia contribute to the greater LTB4, ROS, and iNOS production with APOE4. An extensive recent proteomic and lipidomic investigation in animal brains of ApoE-TR mice corroborates the enhanced eicosanoid signaling with APOE4 [49]. LTB4 signaling may have a prominent role in inducing oxidative stress.…”

Section: Zhu Etmentioning

confidence: 68%

Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4

Solomon

Fonteh

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and the risk of developing late-onset Alzheimer's disease (AD), but the mechanisms for this association are not clear. The activation of calcium-dependent cytosolic phospholipase A2 (cPLA2) is involved in inflammatory signaling and is elevated within the plaques of AD brains. The relation between APOE4 genotype and cPLA2 activity is not known.Methods: Mouse primary astrocytes, mouse and human brain samples differing by APOE genotypes were collected for measuring cPLA2 expression, phosphorylation, and activity in relation to measures of inflammation and oxidative stress. Results: Greater cPLA2 phosphorylation and activity was identified in ApoE4 compared to ApoE3 in primary astrocytes and brains of ApoE-targeted replacement (ApoE-TR) mice. These differences were also demonstrated in brain homogenates from the inferior frontal cortex from AD patients carrying APOE3/4 compared to APOE3/3. Higher cPLA2 activation with APOE4 was associated with greater activation of the MAPK p38 pathway in human postmortem frontal cortical synaptosomes and astrocytes, as well as with higher levels of leukotriene B4 (LTB4), reactive oxygen species (ROS), and inducible nitric oxide synthase (iNOS) in astrocytes. Inhibition of cPLA2 reduced LTB4, ROS, and iNOS levels in ApoE4 primary astrocytes to those in ApoE3 astrocytes. Conclusions: Our findings implicate greater activation of cPLA2 signaling system with APOE4, which could represent a potential drug target for mitigating the increased neuroinflammation with APOE4 and AD.

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“…These mouse models transcribe human APOE alleles from the endogenous murine Apoe promotor: the predominant human allele ε3, the rare AD-protective ε2 allele, and the AD-risk allele, ε4. Zhao et al (2020) performed a comprehensive brain transcriptome profiling experiment across aging in both male and female mice to assess the effect of homozygosity for the ε2 or ε4 alleles relative to the risk-neutral ε3 allele. Since our aim is to identify the early changes occurring due to AD-related mutations, we re-analysed only the 3-month brain samples from the Zhao et al dataset (i.e.…”

Section: Resultsmentioning

confidence: 99%

Comparative analysis of Alzheimer’s disease knock-in model brain transcriptomes implies changes to energy metabolism as a causative pathogenic stress

Barthelson

Newman

Lardelli

2021

Preprint

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Energy production is the most fundamentally important cellular activity supporting all other functions, particularly in highly active organs such as brains, Here we summarise transcriptome analyses of young adult (pre-disease) brains from a collection of eleven early onset familial Alzheimer's disease (EOfAD)-like and non-EOfAD-like mutations in three zebrafish genes. The one cellular activity consistently predicted as affected by only the EOfAD-like mutations is oxidative phosphorylation that produces most of the brain's energy. All the mutations were predicted to affect protein synthesis. We extended our analysis to knock-in mouse models of APOE alleles and found the same effect for the late onset Alzheimer's disease risk allele E4. Our results support a common molecular basis for initiation of the pathological processes leading to both early and late onset forms of Alzheimer's disease and illustrate the utility of both zebrafish and knock-in, single EOfAD mutation models for understanding the causes of this disease.

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Alzheimer's Risk Factors Age, <i>APOE</i> Genotype, and Sex Drive Distinct Molecular Pathways

Cited by 11 publications

References 0 publications

Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4

Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4

Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4

Comparative analysis of Alzheimer’s disease knock-in model brain transcriptomes implies changes to energy metabolism as a causative pathogenic stress

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