APOE and metabolic dysfunction in Alzheimer's disease

Johnson, Lance A.

doi:10.1016/bs.irn.2020.02.002

Cited by 18 publications

(21 citation statements)

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“…Metabolic differences driven by ApoE isoforms are widespread and well documented. 32,33 However, no work that we are aware of has probed the transulfuration pathway or 1-C metabolism related to homocysteine in the context of ApoE isoform differences; though some studies have looked at the incidence of ApoE e4 and HHcy, with conflicting results. 34,35 Ravaglia et al showed human e4 carriers had a lower association with elevated plasma tHcy and a higher level of C-reactive protein, a common marker of generalized inflammation used clinically.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Apolipoprotein E ε4/4 genotype limits response to dietary induction of hyperhomocysteinemia and resulting inflammatory signaling

Seaks

Weekman

Sudduth³

et al. 2022

J Cereb Blood Flow Metab

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Vascular contributions to cognitive impairment and dementia (VCID) are the second leading cause of dementia behind Alzheimer’s disease. Apolipoprotein E (ApoE) is a lipid transporting lipoprotein found within the brain and periphery. The APOE ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease and is a risk factor for VCID. Our lab has previously utilized a dietary model of hyperhomocysteinemia (HHcy) to induce VCID pathology and cognitive deficits in mice. This diet induces perivascular inflammation through cumulative oxidative damage leading to glial mediated inflammation and blood brain barrier breakdown. Here, we examine the impact of ApoE ε4 compared to ε3 alleles on the progression of VCID pathology and inflammation in our dietary model of HHcy. We report a significant resistance to HHcy induction in ε4 mice, accompanied by a number of related differences related to homocysteine (Hcy) metabolism and methylation cycle, or 1-C, metabolites. There were also significant differences in inflammatory profiles between ε3 and ε4 mice, as well as significant reduction in Serpina3n, a serine protease inhibitor associated with ApoE ε4, expression in ε4 HHcy mice relative to ε4 controls. Finally, we find evidence of pervasive sex differences within both genotypes in response to HHcy induction.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E ε4/4 genotype limits response to dietary induction of hyperhomocysteinemia and resulting inflammatory signaling

Seaks

Weekman

Sudduth³

et al. 2022

J Cereb Blood Flow Metab

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“…Based on our data and findings in other cell types (Mahley et al, 2007;Liu et al, 2013;Dose et al, 2016;Fernandez et al, 2019;Butterfield and Mattson, 2020;Flowers and Rebeck, 2020;Johnson, 2020), we present a working model of how APOE genotype could modulate the basal phenotypic state of brain endothelial cells (Figure 12). In this model, we propose that, compared to APOE3, APOE4 brain endothelial cells have higher preference for oxidative phosphorylation over glycolysis, which results in higher mitochondrial activity and generation of mitochondrial reactive oxygen species and lower levels of antioxidants (heme/bilirubin and glutathione).…”

Section: Integrated Working Model Of the Apoe Modulated Brain Endothelial Cell Phenotypementioning

confidence: 94%

Autocrine Effects of Brain Endothelial Cell-Produced Human Apolipoprotein E on Metabolism and Inflammation in vitro

Marottoli

Trevino

Geng

et al. 2021

Front. Cell Dev. Biol.

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Reports of APOE4-associated neurovascular dysfunction during aging and in neurodegenerative disorders has led to ongoing research to identify underlying mechanisms. In this study, we focused on whether the APOE genotype of brain endothelial cells modulates their own phenotype. We utilized a modified primary mouse brain endothelial cell isolation protocol that enabled us to perform experiments without subculture. Through initial characterization we found, that compared to APOE3, APOE4 brain endothelial cells produce less apolipoprotein E (apoE) and have altered metabolic and inflammatory gene expression profiles. Further analysis revealed APOE4 brain endothelial cultures have higher preference for oxidative phosphorylation over glycolysis and, accordingly, higher markers of mitochondrial activity. Mitochondrial activity generates reactive oxygen species, and, with APOE4, there were higher mitochondrial superoxide levels, lower levels of antioxidants related to heme and glutathione and higher markers/outcomes of oxidative damage to proteins and lipids. In parallel, or resulting from reactive oxygen species, there was greater inflammation in APOE4 brain endothelial cells including higher chemokine levels and immune cell adhesion under basal conditions and after low-dose lipopolysaccharide (LPS) treatment. In addition, paracellular permeability was higher in APOE4 brain endothelial cells in basal conditions and after high-dose LPS treatment. Finally, we found that a nuclear receptor Rev-Erb agonist, SR9009, improved functional metabolic markers, lowered inflammation and modulated paracellular permeability at baseline and following LPS treatment in APOE4 brain endothelial cells. Together, our data suggest that autocrine signaling of apoE in brain endothelial cells represents a novel cellular mechanism for how APOE regulates neurovascular function.

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“…Previous studies in humans demonstrated APOE genotype affects metabolism on a cellular, regional, and organismal level [53,54]. To determine whether running and APOE genotype affect metabolic processes, energy expenditure (kcal/hr) was measured at 11mo.…”

Section: Apoe Genotype Affects Running-dependent Increase In Energy E...mentioning

confidence: 99%

APOE^ε4 and exercise interact to influence systemic and cerebral risk factors for dementia

Foley

Diemler

Hewes

et al. 2022

Preprint

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INTRODUCTION: APOEϵ4 is the strongest genetic risk factor for Alzheimers disease and related dementias (ADRDs) affecting many different pathways that lead to cognitive decline. Exercise is one of the most widely proposed prevention, and intervention strategies to mitigate risk and symptomology of ADRDs. Importantly, exercise and APOEϵ4 affect similar processes on the body and brain. While both APOEϵ4, and exercise have been studied extensively, their interactive effects are not well understood. METHODS: To address this, male and female APOEϵ3/ϵ3, APOEϵ3/ϵ4 and APOEϵ4/ϵ4 mice ran voluntarily from wean (1mo) to midlife (12mo). Longitudinal and cross-sectional phenotyping was performed on the periphery and the brain, on markers of risk for dementia such as weight, body composition, circulating cholesterol composition, activities of daily living, energy expenditure, and cortical and hippocampal transcriptional profiling. RESULTS: Data revealed chronic running decreased age-dependent weight gain, lean and fat mass, and serum LDL concentration dependent on APOE genotype. Additionally, murine activities of daily living and energy expenditure were significantly influenced by an interaction between APOE genotype and running in both sexes. Transcriptional profiling of the cortex and hippocampus predicted that APOE genotype and running interact to affect numerous biological processes including vascular integrity, synaptic/neuronal health, cell motility, and mitochondrial metabolism, in a sex-specific manner. DISCUSSION: These data provide compelling evidence that APOE genotype should be considered for population-based strategies that incorporate exercise to prevent ADRDs.

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APOE and metabolic dysfunction in Alzheimer's disease

Cited by 18 publications

References 127 publications

Apolipoprotein E ε4/4 genotype limits response to dietary induction of hyperhomocysteinemia and resulting inflammatory signaling

Apolipoprotein E ε4/4 genotype limits response to dietary induction of hyperhomocysteinemia and resulting inflammatory signaling

Autocrine Effects of Brain Endothelial Cell-Produced Human Apolipoprotein E on Metabolism and Inflammation in vitro

APOE^ε4 and exercise interact to influence systemic and cerebral risk factors for dementia

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APOE and metabolic dysfunction in Alzheimer's disease

Cited by 18 publications

References 127 publications

Apolipoprotein E ε4/4 genotype limits response to dietary induction of hyperhomocysteinemia and resulting inflammatory signaling

Apolipoprotein E ε4/4 genotype limits response to dietary induction of hyperhomocysteinemia and resulting inflammatory signaling

Autocrine Effects of Brain Endothelial Cell-Produced Human Apolipoprotein E on Metabolism and Inflammation in vitro

APOEε4 and exercise interact to influence systemic and cerebral risk factors for dementia

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APOE^ε4 and exercise interact to influence systemic and cerebral risk factors for dementia