| 1. |
- Chernyaeva, Larisa, et al.
(author)
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Reduced binding of apoE4 to complement factor H promotes amyloid-β oligomerization and neuroinflammation
- 2023
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In: EMBO Reports. - 1469-221X. ; 24:7
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Journal article (peer-reviewed)abstract
- The APOE4 variant of apolipoprotein E (apoE) is the most prevalent genetic risk allele associated with late-onset Alzheimer's disease (AD). ApoE interacts with complement regulator factor H (FH), but the role of this interaction in AD pathogenesis is unknown. Here we elucidate the mechanism by which isoform-specific binding of apoE to FH alters Aβ1-42-mediated neurotoxicity and clearance. Flow cytometry and transcriptomic analysis reveal that apoE and FH reduce binding of Aβ1-42 to complement receptor 3 (CR3) and subsequent phagocytosis by microglia which alters expression of genes involved in AD. Moreover, FH forms complement-resistant oligomers with apoE/Aβ1-42 complexes and the formation of these complexes is isoform specific with apoE2 and apoE3 showing higher affinity to FH than apoE4. These FH/apoE complexes reduce Aβ1-42 oligomerization and toxicity, and colocalize with complement activator C1q deposited on Aβ plaques in the brain. These findings provide an important mechanistic insight into AD pathogenesis and explain how the strongest genetic risk factor for AD predisposes for neuroinflammation in the early stages of the disease pathology.
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| 2. |
- Karlsson, Helen, 1961-, et al.
(author)
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Lipids and Lipoproteins in Atherosclerosis / Special issue
- 2011
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In: Journal of Lipids. - : Hindawi Publishing Corporation. - 2090-3030 .- 2090-3049.
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Journal article (peer-reviewed)abstract
- Atherosclerosis is a focal disease of the arterial wall that leads to cardiovascular disease (CVD), the biggest cause of morbidity and mortality in Western societies. Atherosclerosis is a complex, chronic, progressive disease that affects large and medium-sized arteries. Atherosclerotic lesions are promoted by low-density lipoproteins and form from accumulation of fatty substances, cholesterol, cellular waste products, calcium, and fibrin in the inner lining of the arterial wall. Lipoproteins are complexes of amphipathic proteins with lipids at variable ratios, densities, and sizes. Their role is to transport water-insoluble lipids in the blood. Plasma lipoproteins have traditionally been grouped into five major classes, based on their buoyant density: chylomicrons, very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). It is believed that atherogenic lipoproteins, such as LDL and lipoprotein remnants, that float in the VLDL IDL region, promote atherosclerosis, and antiatherogenic lipoproteins, such as HDL, protect from atherosclerosis. Despite many advances in cardiology, atherosclerosis remains an important medical problem suggesting that some steps in pathogenic mechanisms remain unclear.This special issue contains a series of reviews and original research articles that seek to provide insight into the role of lipids and lipoproteins in health and disease with emphasis given on their implication in atherosclerosis.
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| 3. |
- Ljunggren, Stefan A, et al.
(author)
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Lipoprotein profiles in human heterozygote carriers of a functional mutation P297S in scavenger receptor class B1.
- 2015
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In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier. - 1388-1981 .- 1879-2618. ; 1851:12, s. 1587-1595
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Journal article (peer-reviewed)abstract
- The scavenger receptor class B type 1 (SR-B1) is an important HDL receptor involved in cholesterol uptake and efflux, but its physiological role in human lipoprotein metabolism is not fully understood. Heterozygous carriers of the SR-B1P297S mutation are characterized by increased HDL cholesterol levels, impaired cholesterol efflux from macrophages and attenuated adrenal function. Here, the composition and function of lipoproteins were studied in SR-B1P297S heterozygotes.Lipoproteins from six SR-B1P297S carriers and six family controls were investigated. HDL and LDL/VLDL were isolated by ultracentrifugation and proteins were separated by two-dimensional gel electrophoresis and identified by mass spectrometry. HDL antioxidant properties, paraoxonase 1 activities, apoA-I methionine oxidations and HDL cholesterol efflux capacity were assessed.Multivariate modeling separated carriers from controls based on lipoprotein composition. Protein analyses showed a significant enrichment of apoE in LDL/VLDL and of apoL-1 in HDL from heterozygotes compared to controls. The relative distribution of plasma apoE was increased in LDL and in lipid-free form. There were no significant differences in paraoxonase 1 activities, HDL antioxidant properties or HDL cholesterol efflux capacity but heterozygotes showed a significant increase of oxidized methionines in apoA-I.The SR-B1P297S mutation affects both HDL and LDL/VLDL protein compositions. The increase of apoE in carriers suggests a compensatory mechanism for attenuated SR-B1 mediated cholesterol uptake by HDL. Increased methionine oxidation may affect HDL function by reducing apoA-I binding to its targets. The results illustrate the complexity of lipoprotein metabolism that has to be taken into account in future therapeutic strategies aiming at targeting SR-B1.
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| 4. |
- Loch, Rolf Antonie, et al.
(author)
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Cross interactions between Apolipoprotein E and amyloid proteins in neurodegenerative diseases
- 2023
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In: Computational and Structural Biotechnology Journal. - : Elsevier BV. - 2001-0370. ; 21, s. 1189-1204
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Journal article (peer-reviewed)abstract
- Three common Apolipoprotein E isoforms, ApoE2, ApoE3, and ApoE4, are key regulators of lipid homeostasis, among other functions. Apolipoprotein E can interact with amyloid proteins. The isoforms differ by one or two residues at positions 112 and 158, and possess distinct structural conformations and functions, leading to isoform-specific roles in amyloid-based neurodegenerative diseases. Over 30 different amyloid proteins have been found to share similar characteristics of structure and toxicity, suggesting a common interactome. The molecular and genetic interactions of ApoE with amyloid proteins have been extensively studied in neurodegenerative diseases, but have not yet been well connected and clarified. Here we summarize essential features of the interactions between ApoE and different amyloid proteins, identify gaps in the understanding of the interactome and propose the general interaction mechanism between ApoE isoforms and amyloid proteins. Perhaps more importantly, this review outlines what we can learn from the interactome of ApoE and amyloid proteins; that is the need to see both ApoE and amyloid proteins as a basis to understand neurodegenerative diseases.
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