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Associations between brain inflammatory profiles and human neuropathology are altered based on apolipoprotein E ?4 genotype.

ABSTRACT: Alzheimer disease (AD) is a chronic neurodegenerative disease with a multitude of contributing genetic factors, many of which are related to inflammation. The apolipoprotein E (APOE) ?4 allele is the most common genetic risk factor for AD and is related to a pro-inflammatory state. To test the hypothesis that microglia and AD-implicated cytokines were differentially associated with AD pathology based on the presence of APOE ?4, we examined the dorsolateral frontal cortex from deceased participants within a community-based aging cohort (n?=?154). Cellular density of Iba1, a marker of microglia, was positively associated with tau pathology only in APOE ?4 positive participants (p?=?0.001). The cytokines IL-10, IL-13, IL-4, and IL-1? were negatively associated with tau pathology, independent of A?1-42 levels, only in APOE ?4 negative participants. Overall, the association of mostly anti-inflammatory cytokines with less tau pathology suggests a protective effect in APOE ?4 negative participants. These associations are largely absent in the presence of APOE ?4 where tau pathology was significantly associated with increased microglial cell density. Taken together, these results suggest that APOE ?4 mediates an altered inflammatory response and increased tau pathology independent of A?1-42 pathology.

SUBMITTER: Friedberg JS

PROVIDER: S-EPMC7031423 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Associations between brain inflammatory profiles and human neuropathology are altered based on apolipoprotein E ε4 genotype.

Friedberg Jacob S JS Aytan Nurgul N Cherry Jonathan D JD Xia Weiming W Standring Oliver J OJ Alvarez Victor E VE Nicks Raymond R Svirsky Sarah S Meng Gaoyuan G Jun Gyungah G Ryu Hoon H Au Rhoda R Stein Thor D TD

Scientific reports 20200219 1

Alzheimer disease (AD) is a chronic neurodegenerative disease with a multitude of contributing genetic factors, many of which are related to inflammation. The apolipoprotein E (APOE) ε4 allele is the most common genetic risk factor for AD and is related to a pro-inflammatory state. To test the hypothesis that microglia and AD-implicated cytokines were differentially associated with AD pathology based on the presence of APOE ε4, we examined the dorsolateral frontal cortex from deceased participan ...[more]

PMID: 32076055

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Project description:In addition to being the greatest genetic risk factor for Alzheimer's disease, expression of the ?4 allele of apolipoprotein E can lead to cognitive decline during ageing that is independent of Alzheimer's amyloid-? and tau pathology. In human post-mortem tissue and mouse models humanized for apolipoprotein E, we examined the impact of apolipoprotein E4 expression on brain exosomes, vesicles that are produced within and secreted from late-endocytic multivesicular bodies. Compared to humans or mice homozygous for the risk-neutral ?3 allele we show that the ?4 allele, whether homozygous or heterozygous with an ?3 allele, drives lower exosome levels in the brain extracellular space. In mice, we show that the apolipoprotein E4-driven change in brain exosome levels is age-dependent: while not present at age 6 months, it is detectable at 12 months of age. Expression levels of the exosome pathway regulators tumor susceptibility gene 101 (TSG101) and Ras-related protein Rab35 (RAB35) were found to be reduced in the brain at the protein and mRNA levels, arguing that apolipoprotein E4 genotype leads to a downregulation of exosome biosynthesis and release. Compromised exosome production is likely to have adverse effects, including diminishing a cell's ability to eliminate materials from the endosomal-lysosomal system. This reduction in brain exosome levels in 12-month-old apolipoprotein E4 mice occurs earlier than our previously reported brain endosomal pathway changes, arguing that an apolipoprotein E4-driven failure in exosome production plays a primary role in endosomal and lysosomal deficits that occur in apolipoprotein E4 mouse and human brains. Disruption of these interdependent endosomal-exosomal-lysosomal systems in apolipoprotein E4-expressing individuals may contribute to amyloidogenic amyloid-? precursor protein processing, compromise trophic signalling and synaptic function, and interfere with a neuron's ability to degrade material, all of which are events that lead to neuronal vulnerability and higher risk of Alzheimer's disease development. Together, these data suggest that exosome pathway dysfunction is a previously unappreciated component of the brain pathologies that occur as a result of apolipoprotein E4 expression.

Project description:BackgroundApolipoprotein E (APOE) polymorphism is associated with lipid levels. Some studies have reported that blood lipid response to diet or obesity varies depending on APOE genotypes. The aim of this study was to assess the effect of APOE genotypes, the intake of saturated fatty acids (SFA), and obesity on serum lipid levels in Lithuanian adult population.Methodology/principal findingsA cross-sectional health survey was carried out in five municipalities of Lithuania. The random sample was obtained from lists of 25-64 year-old inhabitants registered at primary health care centres. The data from 996 subjects (416 men and 580 women) were analysed in this study. Two single-nucleotide polymorphisms (rs429358 and rs7412) were assessed using a real-time polymerase chain reaction. 24-hour recall and food frequency questionnaire were used for evaluation of dietary habits. Serum lipids were determined using enzymatic methods. Men and women with the APOE2 genotype had the lowest level of total cholesterol (TC) (p = 0.002 for men, and p = 0.02 for women) and low-density lipoprotein cholesterol (LDL-C) (p<0.001). Multivariate linear regression analysis showed that age, genotype APOE2, SFA intake, and body mass index (BMI) were significant determinants of TC and LDL-C level (with p values ranging from 0.043 to 0.001). Our data did not reveal any statistically significant interactions between APOE genotype and SFA intake or between APOE genotype and BMI regarding TC and LDL-C level (all p>0.05). However, the predictive power of the regression model for LDL-C improved when gene-BMI interaction and gene-BMI interaction plus gene-nutrient interaction were added (p = 0.04 and p = 0.032 for R(2) change, respectively).Conclusions/significanceAPOE genotypes, SFA intake, and obesity were found to be associated with blood lipid levels in Lithuanian adult population. Analysis of gene-diet and gene-obesity interactions did not confirm that the effects of diet and obesity on TC and LDL-C level significantly depended on APOE genotype.

Project description:BACKGROUND:Pericytes and endothelial cells are critical cellular components of the blood-brain barrier (BBB) and play an important role in neuroinflammation. To date, the majority of inflammation-related studies in endothelia and pericytes have been carried out using immortalised cell lines or non-human-derived cells. Whether these are representative of primary human cells is unclear and systematic comparisons of the inflammatory responses of primary human brain-derived pericytes and endothelia has yet to be performed. METHODS:To study the effects of neuroinflammation at the BBB, primary brain endothelial cells and pericytes were isolated from human biopsy tissue. Culture purity was examined using qPCR and immunocytochemistry. Electrical cell-substrate impedance sensing (ECIS) was used to determine the barrier properties of endothelial and pericyte cultures. Using immunocytochemistry, cytometric bead array, and ECIS, we compared the responses of endothelia and pericytes to a panel of inflammatory stimuli (IL-1β, TNFα, LPS, IFN-γ, TGF-β1, IL-6, and IL-4). Secretome analysis was performed to identify unique secretions of endothelia and pericytes in response to IL-1β. RESULTS:Endothelial cells were pure, moderately proliferative, retained the expression of BBB-related junctional proteins and transporters, and generated robust TEER. Both endothelia and pericytes have the same pattern of transcription factor activation in response to inflammatory stimuli but respond differently at the secretion level. Secretome analysis confirmed that endothelia and pericytes have overlapping but distinct secretome profiles in response to IL-1β. We identified several cell-type specific responses, including G-CSF and GM-CSF (endothelial-specific), and IGFBP2 and IGFBP3 (pericyte-specific). Finally, we demonstrated that direct addition of IL-1β, TNFα, LPS, and IL-4 contributed to the loss of endothelial barrier integrity in vitro. CONCLUSIONS:Here, we identify important cell-type differences in the inflammatory response of brain pericytes and endothelia and provide, for the first time, a comprehensive profile of the secretions of primary human brain endothelia and pericytes which has implications for understanding how inflammation affects the cerebrovasculature.

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Associations between brain inflammatory profiles and human neuropathology are altered based on apolipoprotein E ?4 genotype.

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Associations between brain inflammatory profiles and human neuropathology are altered based on apolipoprotein E ε4 genotype.

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