RESUMEN
Apolipoprotein E (APOE) genetic variants are most notably known for their divergent impact on the risk of developing Alzheimer's disease. While APOE genotype has been consistently shown to modulate lipid metabolism in a variety of cellular contexts, the effect of APOE alleles on the lipidome in hepatocytes is unknown. In this study, we investigated the contribution of APOE alleles to lipidomic profiles of donor-derived primary human hepatocytes from 77 subjects. Lipidomic data obtained by liquid chromatography-mass spectrometry were analyzed across ε2/ε3, ε3/ε3, and ε3/ε4 genotypes to reveal how APOE modulates lipid relative levels over age and between groups. Hepatic APOE concentration, measured by ELISA, was assessed for correlation with lipid abundance in subjects grouped as per APOE genotype and sex. APOE genotype-specific differential lipidomic signatures associated with age for multiple lipid classes but did not differ between sexes. Compared to ε2/ε3, ε3/ε4 hepatocytes had higher abundance of acylcarnitines (AC) and acylphosphatidylglycerol (AcylPG) as a class, as well as higher medium and long-chain ACs, AcylPG, phosphatidylglycerol (PG), bis(monoacylglycerol)phosphate (BMP), monoacylglycerol (MG) and diacylglycerol (DG) species. The ε3/ε4 hepatocytes also exhibited a higher abundance of medium and long-chain ACs compared to the ε3/ε3 hepatocytes. Only in the ε3/ε4 hepatocytes, APOE concentration was lower and showed a negative correlation with BMP levels, specifically in females. APOE genotype dictates a differential lipidome in primary human hepatocytes. The lipids involved suggest mitochondrial dysfunction with accompanying alterations in neutral lipid storage, reflective of a general disturbance of free fatty acid metabolism in human hepatocytes with the ε4 allele.
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Apolipoproteínas E , Lipidómica , Femenino , Humanos , Alelos , Apolipoproteínas E/genética , Genotipo , HepatocitosRESUMEN
Liver-generated plasma apolipoprotein E (apoE) does not enter the brain but nonetheless correlates with Alzheimer's disease (AD) risk and AD biomarker levels. Carriers of APOEε4, the strongest genetic AD risk factor, exhibit lower plasma apoE and altered brain integrity already at mid-life versus non-APOEε4 carriers. Whether altered plasma liver-derived apoE or specifically an APOEε4 liver phenotype promotes neurodegeneration is unknown. Here we investigated the brains of Fah-/-, Rag2-/-, Il2rg-/- mice on the Non-Obese Diabetic (NOD) background (FRGN) with humanized-livers of an AD risk-associated APOE ε4/ε4 versus an APOE ε2/ε3 genotype. Reduced endogenous mouse apoE levels in the brains of APOE ε4/ε4 liver mice were accompanied by various changes in markers of synaptic integrity, neuroinflammation and insulin signaling. Plasma apoE4 levels were associated with unfavorable changes in several of the assessed markers. These results propose a previously unexplored role of the liver in the APOEε4-associated risk of neurodegenerative disease.
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Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Animales , Ratones , Apolipoproteína E4/genética , Ratones Endogámicos NOD , Apolipoproteínas E/genética , Encéfalo/metabolismo , Enfermedad de Alzheimer/genética , Genotipo , Biomarcadores , Hígado/metabolismoRESUMEN
INTRODUCTION: At the Alzheimer's Association's APOE and Immunity virtual conference, held in October 2021, leading neuroscience experts shared recent research advances on and inspiring insights into the various roles that both the apolipoprotein E gene (APOE) and facets of immunity play in neurodegenerative diseases, including Alzheimer's disease and other dementias. METHODS: The meeting brought together more than 1200 registered attendees from 62 different countries, representing the realms of academia and industry. RESULTS: During the 4-day meeting, presenters illuminated aspects of the cross-talk between APOE and immunity, with a focus on the roles of microglia, triggering receptor expressed on myeloid cells 2 (TREM2), and components of inflammation (e.g., tumor necrosis factor α [TNFα]). DISCUSSION: This manuscript emphasizes the importance of diversity in current and future research and presents an integrated view of innate immune functions in Alzheimer's disease as well as related promising directions in drug development.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/patología , Microglía/patología , Inflamación , Apolipoproteínas E/genéticaRESUMEN
Neurodegenerative diseases are characterized by the aggregation and deposition of misfolded proteins in the brain, most prominently amyloid-ß (Aß), tau and α-synuclein (α-syn), and are thus referred to as proteinopathies. While tau is a hallmark of Alzheimer's disease (AD) and other non-AD tauopathies, and α-synuclein is the pathological feature of the spectrum of synucleinopathies including Parkinson's disease (PD), Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB), the presence of co-pathologies is very frequent in all these diseases. Positive and synergistic associations between the different types of protein deposits have been reported, leading to worse prognosis and cognitive decline. A large variation in phenotypic clinical presentation of these diseases, largely due to the frequent presence of co-pathologies, makes differential diagnosis challenging. The observed clinico-pathological overlaps suggest common underlying mechanisms, in part due to shared genetic risk factors. The ε4 allele of the apolipoprotein (APOE) gene is one of the major genetic risk factors for the sporadic forms of proteinopathies, but the biological mechanisms linking APOE, tau and α-syn are not fully understood. This chapter describes current experimental evidence on the relationships between APOE variants, tau and α-syn, from clinical studies on fluid biomarkers and positron emission tomography (PET) imaging, and from basic experimental studies in cellular/molecular biology and animal models. The chapter focuses on recent advances and identifies knowledge gaps. In particular, no PET tracer for assessment of brain α-syn deposits is yet available, although it is subject of intense research and development, therefore experimental evidence on in vivo α-syn levels is based on measures in the cerebrospinal fluid (CSF) and plasma. Moreover, tau PET imaging studies comparing the patterns of tracer retention in synucleinopathies versus in other proteinopathies are scarce and much is still unknown regarding the relationships between APOE variants and fluid and/or imaging biomarkers of tau and α-syn. Further research incorporating multimodal imaging, fluid biomarkers and genetic factors will help elucidate the biological mechanisms underlying these proteinopathies, and contribute to differential diagnosis and patient stratification for clinical trials.
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Apolipoproteínas E/genética , Sinucleinopatías/genética , Sinucleinopatías/metabolismo , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Biomarcadores/análisis , Biomarcadores/metabolismo , Humanos , Enfermedad por Cuerpos de Lewy/genética , Enfermedad por Cuerpos de Lewy/metabolismo , Enfermedad por Cuerpos de Lewy/patología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Sinucleinopatías/patologíaRESUMEN
BACKGROUND: Dysregulation of the specialized lipid metabolism involved in myelin synthesis and maintenance by oligodendrocytes has been associated with the unique neuropathology of MSA. We hypothesized that apolipoprotein E, which is associated with neurodegeneration, may also play a role in the pathogenesis of MSA. OBJECTIVE: This study evaluated genetic associations of Apolipoprotein E alleles with risk of MSA and α-synuclein pathology, and also examined whether apolipoprotein E isoforms differentially affect α-synuclein uptake in a oligodendrocyte cell. METHODS: One hundred sixty-eight pathologically confirmed MSA patients, 89 clinically diagnosed MSA patients, and 1,277 control subjects were genotyped for Apolipoprotein E. Human oligodendrocyte cell lines were incubated with α-synuclein and recombinant human apolipoprotein E, with internalized α-synuclein imaged by confocal microscopy and cells analyzed by flow cytometry. RESULTS: No significant association with risk of MSA or was observed for either Apolipoprotein E É2 or É4. α-Synuclein burden was also not associated with Apolipoprotein E alleles in the pathologically confirmed patients. Interestingly, in our cell assays, apolipoprotein E É4 significantly reduced α-synuclein uptake in the oligodendrocytic cell line. CONCLUSIONS: Despite differential effects of apolipoprotein E isoforms on α-synuclein uptake in a human oligodendrocytic cell, we did not observe a significant association at the Apolipoprotein E locus with risk of MSA or α-synuclein pathology. © 2018 International Parkinson and Movement Disorder Society.
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Apolipoproteínas E/genética , Atrofia de Múltiples Sistemas/genética , alfa-Sinucleína/metabolismo , Anciano , Astrocitos/metabolismo , Línea Celular Transformada , Femenino , Pruebas Genéticas , Genotipo , Humanos , MasculinoRESUMEN
Apolipoprotein E (apoE) is the major cholesterol transport protein in the brain. Among the three human APOE alleles (APOE2, APOE3, and APOE4), APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease (AD). The accumulation of amyloid-ß (Aß) is a central event in AD pathogenesis. Increasing evidence demonstrates that apoE isoforms differentially regulate AD-related pathways through both Aß-dependent and -independent mechanisms; therefore, modulating apoE secretion, lipidation, and function might be an attractive approach for AD therapy. We performed a drug screen for compounds that modulate apoE production in immortalized astrocytes derived from apoE3-targeted replacement mice. Here, we report that retinoic acid (RA) isomers, including all-trans-RA, 9-cis-RA, and 13-cis-RA, significantly increase apoE secretion to ~4-fold of control through retinoid X receptor (RXR) and RA receptor. These effects on modulating apoE are comparable with the effects recently reported for the RXR agonist bexarotene. Furthermore, all of these compounds increased the expression of the cholesterol transporter ABCA1 and ABCG1 levels and decreased cellular uptake of Aß in an apoE-dependent manner. Both bexarotene and 9-cis-RA promote the lipidation status of apoE, in which 9-cis-RA promotes a stronger effect and exhibits less cytotoxicity compared with bexarotene. Importantly, we showed that oral administration of bexarotene and 9-cis-RA significantly increases apoE, ABCA1, and ABCG1 levels in mouse brains. Taken together, our results demonstrate that RXR/RA receptor agonists, including several RA isomers, are effective modulators of apoE secretion and lipidation and may be explored as potential drugs for AD therapy.
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Enfermedad de Alzheimer/metabolismo , Apolipoproteínas E/metabolismo , Astrocitos/metabolismo , Lipoilación , Proteínas del Tejido Nervioso/metabolismo , Receptores de Ácido Retinoico/metabolismo , Receptores X Retinoide/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1 , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Alelos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Animales , Anticarcinógenos/farmacología , Apolipoproteínas E/genética , Astrocitos/patología , Bexaroteno , Encéfalo/metabolismo , Encéfalo/patología , Línea Celular Transformada , Humanos , Lipoproteínas/genética , Lipoproteínas/metabolismo , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Receptores de Ácido Retinoico/genética , Receptores X Retinoide/genética , Tetrahidronaftalenos/farmacología , Tretinoina/análogos & derivados , Tretinoina/farmacologíaRESUMEN
Apolipoprotein E (ApoE) is a polymorphic protein that plays a major role in lipid metabolism in the central nervous system and periphery. It has three common allelic isoforms, ApoE2, ApoE3, and ApoE4, that differ in only one or two amino acids. ApoE isoforms have been associated with the occurrence and progression of several pathological conditions, such as coronary atherosclerosis and Alzheimer's disease. The aim of this study was to develop a mass spectrometry (MS)-based assay for absolute quantification of ApoE isoforms in cerebrospinal fluid and plasma samples using isotope-labeled peptides. The assay included five tryptic peptides: CLAVYQAGAR (ApoE2), LGADMEDVCGR (ApoE2 and 3), LAVYQAGAR (ApoE3 and 4), LGADMEDVR (ApoE4), and LGPLVEQGR (total ApoE). Both cerebrospinal fluid and plasma samples were assayed to validate the method. The digestion yield and the extension of chemical modifications in selected amino acid residues (methionine oxidation, glutamine deamidation, and cyclization of N-terminus carbamidomethylcysteine) were also studied. The ApoE phenotype was successfully assigned to all samples analyzed in a blinded manner. The method showed good linearity (R(2) > 0.99) and reproducibility (within laboratory imprecision <13%). The comparison of the MS-based assay with an ELISA for total ApoE concentration showed a moderate correlation (R(2) = 0.59). This MS-based assay can serve as an important tool in clinical studies aiming to elucidate the association between ApoE genotype, total ApoE, and ApoE isoform concentrations in various disorders related to ApoE polymorphisms.
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Apolipoproteínas E/química , Péptidos/química , Isoformas de Proteínas/química , Secuencia de Aminoácidos , Apolipoproteínas E/análisis , Cromatografía Liquida , Espectrometría de Masas , Datos de Secuencia Molecular , Oxidación-Reducción , Isoformas de Proteínas/análisis , Tripsina/químicaRESUMEN
Defective clearance of the amyloid-ß peptide (Aß) from the brain is considered a strong promoter in Alzheimer's disease (AD) pathogenesis. Astrocytes and microglia are important mediators of Aß clearance and Aß aggregation state and the presence of amyloid associated proteins (AAPs), such as Apolipoproteins E and J (ApoE and ApoJ), may influence Aß clearance by these cells. Here we set out to investigate whether astrocytes and microglia differ in uptake efficiency of Aß oligomers (Aßoligo ) and Aß fibrils (Aßfib ), and whether the Aß aggregation state and/or presence of AAPs affect Aß uptake in these cells in vitro. Adult human primary microglia and astrocytes, isolated from short delay post-mortem brain tissue, were exposed to either Aßoligo or Aßfib alone or combined with a panel of certain AAPs whereafter Aß-positive cells were quantified using flow cytometry. Upon exposure to Aß combined with ApoE, ApoJ, α1-antichymotrypsin (ACT) and a combination of serum amyloid P and complement C1q (SAP-C1q), a clear reduction in astrocytic but not microglial Aßoligo uptake, was observed. In contrast, Aßfib uptake was strongly reduced in the presence of AAPs in microglia, but not in astrocytes. These data provide the first evidence of distinct roles of microglia and astrocytes in Aß clearance. More importantly we show that Aß clearance by glial cells is negatively affected by AAPs like ApoE and ApoJ. Thus, targeting the association of Aß with AAPs, such as ApoE and ApoJ, could serve as a therapeutic strategy to increase Aß clearance by glial cells.
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Péptidos beta-Amiloides/metabolismo , Apolipoproteínas E/metabolismo , Astrocitos/metabolismo , Clusterina/metabolismo , Microglía/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/citología , Células Cultivadas , Femenino , Citometría de Flujo , Humanos , L-Lactato Deshidrogenasa/metabolismo , Masculino , Persona de Mediana Edad , Proteínas del Tejido Nervioso/metabolismo , Unión Proteica , Adulto JovenRESUMEN
The apolipoprotein E (ApoE) ε4 allele is the strongest risk factor of sporadic Alzheimer's disease (AD), however, the fluid concentrations of ApoE and its different isoforms (ApoE2, ApoE3 and ApoE4) in AD patients and among APOE genotypes (APOE ε2, ε3, ε4) remain controversial. Using a novel mass spectrometry-based method, we quantified total ApoE and specific ApoE isoform concentrations and potential associations with age, cognitive status, cholesterol levels and established AD biomarkers in cerebrospinal fluid (CSF) from AD patients versus non-AD individuals with different APOE genotypes. We also investigated plasma total ApoE and ApoE isoform composition in a subset of these individuals. In total n = 43 AD and n = 43 non-AD subjects were included. We found that CSF and plasma total ApoE levels did not correlate with age or cognitive status and did not differ between AD and non-AD subjects deeming ApoE as an unfit diagnostic marker for AD. Also, whereas CSF ApoE levels did not vary between APOE genotypes APOE ε4 carriers exhibited significantly decreased plasma ApoE levels attributed to a specific decrease in the ApoE4 isoform concentrations. CSF total ApoE concentrations were positively associated with CSF, total tau, tau phosphorylated at Thr181 and Aß1-42 of which the latter association was weaker and only present in APOE ε4 carriers indicating a differential involvement of ApoE in tau versus Aß-linked neuropathological processes. Future studies need to elucidate whether the observed plasma ApoE4 deficiency is a life-long condition in APOE É4 carriers and whether this decrease in plasma ApoE predisposes APOE É4 carriers to AD.
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Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/líquido cefalorraquídeo , Apolipoproteínas E/sangre , Apolipoproteínas E/líquido cefalorraquídeo , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/líquido cefalorraquídeo , Apolipoproteína E2/sangre , Apolipoproteína E2/líquido cefalorraquídeo , Apolipoproteína E2/genética , Apolipoproteína E3/sangre , Apolipoproteína E3/líquido cefalorraquídeo , Apolipoproteína E3/genética , Apolipoproteína E4/sangre , Apolipoproteína E4/líquido cefalorraquídeo , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Biomarcadores/líquido cefalorraquídeo , Colesterol/sangre , Colesterol/líquido cefalorraquídeo , Cognición , Femenino , Genotipo , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Fragmentos de Péptidos/líquido cefalorraquídeo , Fosforilación , Proteínas tau/líquido cefalorraquídeoRESUMEN
Neuroinflammation may be involved in the pathophysiology of Parkinson's disease (PD) and specifically in non-motor symptoms such as depression, fatigue and cognitive impairment. The aim of this study was to measure inflammatory markers in cerebrospinal fluid (CSF) samples from PD patients and a reference group, and to investigate correlations between non-motor symptoms and inflammation. We quantified C-reactive protein (CRP), interleukin-6, tumor necrosis factor-alpha, eotaxin, interferon gamma-induced protein-10, monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein 1-ß in CSF samples from PD patients (N=87) and the reference group (N=33). Sixteen of the PD patients had a dementia diagnosis (PDD). We assessed symptoms of fatigue, depression, anxiety and cognitive function using the Functional Assessment of Chronic Illness Therapy-Fatigue, the Hospital Anxiety and Depression Scale, and the Mini Mental State Examination, respectively. There were no significant differences in mean levels of inflammatory markers between PD patients and the reference group. After controlling for age, gender and somatic illness, patients with PDD had significantly higher levels of CRP compared to non-demented PD patients (p=0.032) and the reference group (p=0.026). Increased levels of inflammatory markers in CSF were significantly associated with more severe symptoms of depression, anxiety, fatigue, and cognition in the entire PD group. After controlling for PD duration, age, gender, somatic illness and dementia diagnosis, high CRP levels were significantly associated with more severe symptoms of depression (p=0.010) and fatigue (p=0.008), and high MCP-1 levels were significantly associated with more severe symptoms of depression (p=0.032). Our results indicate that non-motor features of PD such as depression, fatigue, and cognitive impairment are associated with higher CSF levels of inflammatory markers.
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Trastornos del Conocimiento/líquido cefalorraquídeo , Depresión/líquido cefalorraquídeo , Fatiga/líquido cefalorraquídeo , Mediadores de Inflamación/líquido cefalorraquídeo , Enfermedad de Parkinson/líquido cefalorraquídeo , Anciano , Proteína C-Reactiva/líquido cefalorraquídeo , Quimiocina CCL11/líquido cefalorraquídeo , Quimiocina CCL2/líquido cefalorraquídeo , Quimiocina CCL24/líquido cefalorraquídeo , Quimiocina CCL26 , Quimiocina CCL3/líquido cefalorraquídeo , Quimiocina CCL4/líquido cefalorraquídeo , Quimiocinas CC/líquido cefalorraquídeo , Trastornos del Conocimiento/complicaciones , Demencia/líquido cefalorraquídeo , Demencia/complicaciones , Demencia/diagnóstico , Depresión/complicaciones , Fatiga/complicaciones , Femenino , Humanos , Interleucina-6/líquido cefalorraquídeo , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico , Factor de Necrosis Tumoral alfa/líquido cefalorraquídeoRESUMEN
Plasma apolipoprotein E levels were previously associated with the risk of developing Alzheimer's disease (AD), levels of cerebrospinal fluid AD biomarkers, cognition and imaging brain measures. Outside the brain, the liver is the primary source of apoE and liver transplantation studies have demonstrated that liver-derived apoE does not cross the blood-brain-barrier. How hepatic apoE may be implicated in behavioral and cognitive performance is not clear. In the current study, we behaviorally tested FRGN mice with humanized liver harboring the ε3/ε3 genotype (E3-human liver (HL)) and compared their behavioral and cognitive performance with that of age-matched ε3/ε3 targeted replacement (E3-TR) mice, the latter produces human apoE3 throughout the body whereas the E3-HL mice endogenously produce human apoE3 only in the liver. We also compared the liver weights and plasma apoE levels, and assessed whether plasma apoE levels were correlated with behavioral or cognitive measures in both models. E3-HL were more active but performed cognitively worse than E3-TR mice. E3-HL mice moved more in the open field containing objects, showed higher activity levels in the Y maze, showed higher activity levels during the baseline period in the fear conditioning test than E3-TR mice, and swam faster than E3-TR mice during training to locate the visible platform in the water maze. However, E3-HL mice showed reduced spatial memory retention in the water maze and reduced fear learning and contextual and cued fear memory than E3-TR mice. Liver weights were greater in E3-HL than E3-TR mice and sex-dependent only in the latter model. Plasma apoE3 levels were similar to those found in humans and comparable in female and male E3-TR mice but higher in female E3-HL mice. Finally, we found correlations between plasma apoE levels and behavioral and cognitive measures which were predominantly model-dependent. Our study demonstrates mouse-model dependent associations between plasma apoE levels, behavior and cognition in an 'AD-neutral' setting and suggests that a humanized liver might be sufficient to induce mouse behavioral and cognitive phenotypes.
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Enfermedad de Alzheimer , Hígado , Femenino , Masculino , Animales , Humanos , Ratones , Apolipoproteína E3 , Apolipoproteínas E/genética , Cognición , Encéfalo , Enfermedad de Alzheimer/genéticaRESUMEN
BACKGROUND: The APOEε4-promoted risk of Alzheimer's disease (AD) is lower in Black/African-Americans (B/AAs), compared to non-Hispanic whites (NHWs). Previous studies reported lower plasma apolipoprotein E (apoE) levels in NHW APOEε4-carriers compared to non-carriers, and low plasma apoE levels were directly associated with an increased risk of AD and all dementia. We further showed that APOEε3/ε3 AD patients exhibited reduced plasma apoE dimers compared to corresponding control subjects. Whether plasma apoE levels and apoE dimer formation differ between races/ethnicities and therefore may help explain AD risk racial disparity remains to be elucidated. METHODS: Using mass spectrometry, we determined total plasma apoE and apoE isoform levels in a cohort of B/AAs (n = 58) and NHWs (n = 67) including subjects with normal cognition (B/AA: n = 25, NHW: n = 28), mild cognitive impairment (MCI) (B/AA: n = 24, NHW: n = 24), or AD dementia (B/AA: n = 9, NHW: n = 15). Additionally, we used non-reducing western blot analysis to assess the distribution of plasma apoE into monomers/disulfide-linked dimers. Plasma total apoE, apoE isoform levels, and % apoE monomers/dimers were assessed for correlations with cognition, cerebrospinal fluid (CSF) AD biomarkers, sTREM2, neurofilament light protein (NfL), and plasma lipids. RESULTS: Plasma apoE was predominantly monomeric in both racial groups and the monomer/dimer distribution was not affected by disease status, or correlated with CSF AD biomarkers, but associated with plasma lipids. Plasma total apoE levels were not related to disease status and only in the NHW subjects we observed lower plasma apoE levels in the APOEε4/ε4-carriers. Total plasma apoE levels were 13% higher in B/AA compared to NHW APOEε4/ε4 subjects and associated with plasma high-density lipoprotein (HDL) in NHW subjects but with low-density lipoprotein levels (LDL) in the B/AA subjects. Higher plasma apoE4 levels, exclusively in APOEε3/ε4 B/AA subjects, were linked to higher plasma total cholesterol and LDL levels. In the controls, NHWs and B/AAs exhibited opposite associations between plasma apoE and CSF t-tau. CONCLUSIONS: The previously reported lower APOEε4-promoted risk of AD in B/AA subjects may be associated with differences in plasma apoE levels and lipoprotein association. Whether differences in plasma apoE levels between races/ethnicities result from altered APOEε4 expression or turnover, needs further elucidation.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Apolipoproteína E4/líquido cefalorraquídeo , Apolipoproteínas E/genética , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , Proteínas de Neurofilamentos , Isoformas de Proteínas , Proteínas tau/líquido cefalorraquídeo , Negro o Afroamericano , BlancoRESUMEN
ApoE is the major lipid and cholesterol carrier in the CNS. There are three major human polymorphisms, apoE2, apoE3, and apoE4, and the genetic expression of APOE4 is one of the most influential risk factors for the development of late-onset Alzheimer's disease (AD). Neuroinflammation has become the third hallmark of AD, together with Amyloid-ß plaques and neurofibrillary tangles of hyperphosphorylated aggregated tau protein. This review aims to broadly and extensively describe the differential aspects concerning apoE. Starting from the evolution of apoE to how APOE's single-nucleotide polymorphisms affect its structure, function, and involvement during health and disease. This review reflects on how APOE's polymorphisms impact critical aspects of AD pathology, such as the neuroinflammatory response, particularly the effect of APOE on astrocytic and microglial function and microglial dynamics, synaptic function, amyloid-ß load, tau pathology, autophagy, and cell-cell communication. We discuss influential factors affecting AD pathology combined with the APOE genotype, such as sex, age, diet, physical exercise, current therapies and clinical trials in the AD field. The impact of the APOE genotype in other neurodegenerative diseases characterized by overt inflammation, e.g., alpha- synucleinopathies and Parkinson's disease, traumatic brain injury, stroke, amyotrophic lateral sclerosis, and multiple sclerosis, is also addressed. Therefore, this review gathers the most relevant findings related to the APOE genotype up to date and its implications on AD and CNS pathologies to provide a deeper understanding of the knowledge in the APOE field.
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Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Humanos , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Apolipoproteína E2/genética , Apolipoproteína E3/genética , Apolipoproteína E4/genética , Apolipoproteínas E/metabolismo , Genotipo , Enfermedades Neurodegenerativas/genética , Placa Amiloide/patología , Proteínas tau/genéticaRESUMEN
BACKGROUND: Low levels of plasma apolipoprotein E (apoE) and presence of the APOE ε4 allele are associated with an increased risk of Alzheimer's disease (AD). Although the increased risk of AD in APOE ε4-carriers is well-established, the protein levels have received limited attention. METHODS: We here report the total plasma apoE and apoE isoform levels at baseline from a longitudinally (24 months) followed cohort including controls (n = 39), patients with stable amnestic mild cognitive impairment during 24 months follow up (MCI-MCI, n = 30), patients with amnestic MCI (aMCI) that during follow-up were clinically diagnosed with AD with dementia (ADD) (MCI-ADD, n = 28), and patients with AD with dementia (ADD) at baseline (ADD, n = 28). We furthermore assessed associations between plasma apoE levels with cerebrospinal fluid (CSF) AD biomarkers and α-synuclein, as well as both CSF and plasma neurofilament light chain (NfL), YKL-40 and kallikrein 6. RESULTS: Irrespective of clinical diagnosis, the highest versus the lowest apoE levels were found in APOE ε2/ε3 versus APOE ε4/ε4 subjects, with the most prominent differences exhibited in females. Total plasma apoE levels were 32% and 21% higher in the controls versus MCI-ADD and ADD patients, respectively. Interestingly, MCI-ADD patients exhibited a 30% reduction in plasma apoE compared to MCI-MCI patients. This decrease appeared to be associated with brain amyloid-ß (Aß42) pathology regardless of disease status as assessed using the Amyloid, Tau, and Neurodegeneration (A/T/N) classification. In addition to the association between low plasma apoE and low levels of CSF Aß42, lower apoE levels were also related to higher levels of CSF total tau (t-tau) and tau phosphorylated at Threonine 181 residue (p-tau) and NfL as well as a worse performance on the mini-mental-state-examination. In MCI-ADD patients, low levels of plasma apoE were associated with higher levels of CSF α-synuclein and kallikrein 6. No significant correlations between plasma apoE and the astrocytic inflammatory marker YKL40 were observed. CONCLUSIONS: Our results demonstrate important associations between low plasma apoE levels, Aß pathology, and progression from aMCI to a clinical ADD diagnosis.
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Enfermedad de Alzheimer , Apolipoproteínas E , Disfunción Cognitiva , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/líquido cefalorraquídeo , Apolipoproteína E3/líquido cefalorraquídeo , Apolipoproteína E3/genética , Apolipoproteína E4/líquido cefalorraquídeo , Apolipoproteína E4/genética , Apolipoproteínas E/líquido cefalorraquídeo , Apolipoproteínas E/genética , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico , Femenino , Humanos , Calicreínas , Fragmentos de Péptidos/líquido cefalorraquídeo , alfa-Sinucleína , Proteínas tau/líquido cefalorraquídeoRESUMEN
BACKGROUND: Altered cerebral glucose metabolism, especially prominent in APOE É4 carriers, occurs years prior to symptoms in Alzheimer's disease (AD). We recently found an association between a higher ratio of plasma apolipoprotein E4 (apoE4) over apoE3, and cerebral glucose hypometabolism in cognitively healthy APOE É3/É4 subjects. Plasma apoE does not cross the blood-brain barrier, hence we speculate that apoE is linked to peripheral glucose metabolism which is known to affect glucose metabolism in the brain. OBJECTIVE: Explore potential associations between levels of plasma insulin and glucose with previously acquired plasma apoE, cerebral metabolic rate of glucose (CMRgl), gray matter volume, and neuropsychological test scores. METHODS: Plasma insulin and glucose levels were determined by ELISA and a glucose oxidase assay whereas apoE levels were earlier quantified by mass-spectrometry in 128 cognitively healthy APOE É3/É4 subjects. Twenty-five study subjects had previously undergone FDG-PET and structural MRI. RESULTS: Lower plasma apoE3 associated with higher plasma glucose but not insulin in male subjects and subjects with a body mass index above 25. Negative correlations were found between plasma glucose and CMRgl in the left prefrontal and bilateral occipital regions. These associations may have functional implications since glucose levels in turn were negatively associated with neuropsychological test scores. CONCLUSION: Plasma apoE3 but not apoE4 may be involved in insulin-independent processes governing plasma glucose levels. Higher plasma glucose, which negatively affects brain glucose metabolism, was associated with lower plasma apoE levels in APOE É3/É4 subjects. High plasma glucose and low apoE levels may be a hazardous combination leading to an increased risk of AD.
Asunto(s)
Apolipoproteína E3/sangre , Apolipoproteína E4/genética , Glucemia/análisis , Anciano , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Apolipoproteína E3/genética , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Femenino , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/metabolismo , Heterocigoto , Humanos , Insulina/sangre , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas NeuropsicológicasRESUMEN
Intracerebral accumulation of amyloid-beta (A beta) leading to A beta plaque formation, is the main hallmark of Alzheimer's disease and might be caused by defective A beta-clearance. We previously found primary human astrocytes and microglia able to bind and ingest A beta 1-42 in vitro, which appeared to be limited by A beta 1-42 fibril formation. We now confirm that astrocytic A beta-uptake depends on size and/or composition of A beta-aggregates as astrocytes preferably take up oligomeric A beta over fibrillar A beta. Upon exposure to either fluorescence-labelled A beta 1-42 oligomers (A beta(oligo)) or fibrils (A beta(fib)), a larger (3.7 times more) proportion of astrocytes ingested oligomers compared to fibrils, as determined by flow cytometry. A beta-internalization was verified using confocal microscopy and live-cell imaging. Neither uptake of A beta(oligo) nor A beta(fib), triggered proinflammatory activation of the astrocytes, as judged by quantification of interleukin-6 and monocyte-chemoattractant protein-1 release. Amyloid-associated proteins, including alpha1-antichymotrypsin (ACT), serum amyloid P component (SAP), C1q and apolipoproteins E (ApoE) and J (ApoJ) were earlier found to influence A beta-aggregation. Here, astrocytic uptake of A beta(fib) increased when added to the cells in combination with SAP and C1q (SAP/C1q), but was unchanged in the presence of ApoE, ApoJ and ACT. Interestingly, ApoJ and ApoE dramatically reduced the number of A beta(oligo)-positive astrocytes, whereas SAP/C1q slightly reduced A beta(oligo) uptake. Thus, amyloid-associated proteins, especially ApoJ and ApoE, can alter A beta-uptake in vitro and hence may influence A beta clearance and plaque formation in vivo.
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Péptidos beta-Amiloides/metabolismo , Amiloide/metabolismo , Astrocitos/metabolismo , Fragmentos de Péptidos/metabolismo , Apolipoproteínas E/metabolismo , Astrocitos/inmunología , Astrocitos/ultraestructura , Western Blotting , Muerte Celular/fisiología , Células Cultivadas , Quimiocina CCL2/metabolismo , Clusterina/metabolismo , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Humanos , Interleucina-6/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Microscopía Confocal , Microscopía Electrónica , Multimerización de ProteínaRESUMEN
Clearance of the amyloid-beta peptide (A beta) as a remedy for Alzheimer's disease (AD) is a major target in on-going clinical trials. In vitro studies confirmed that A beta is taken up by rodent astrocytes, but knowledge on human astrocyte-mediated A beta clearance is sparse. Therefore, by means of flow cytometry and confocal laser scanning microscopy (CLSM), we evaluated the binding and internalization of A beta1-42 by primary human fetal astrocytes and adult astrocytes, isolated from nondemented subjects (n = 8) and AD subjects (n = 6). Furthermore, we analyzed whether alpha1-antichymotrypsin (ACT), which is found in amyloid plaques and can influence A beta fibrillogenesis, affects the A beta uptake by human astrocytes. Upon over night exposure of astrocytes to FAM-labeled A beta1-42 (10 microM) preparations, (80.7 +/- 17.7)% fetal and (52.9 +/- 20.9)% adult A beta-positive astrocytes (P = 0.018) were observed. No significant difference was found in A beta1-42 uptake between AD and non-AD astrocytes, and no influence of ApoE genotype on A beta1-42 uptake was observed in any group. There was no difference in the percentage of A beta-positive cells upon exposure to A beta1-42 (10 microM) combined with ACT (1,000:1, 100:1, and 10:1 molar ratio), versus A beta1-42 alone. CLSM revealed binding of A beta1-42 to the cellular surfaces and cellular internalization of smaller A beta1-42 fragments. Under these conditions, there was no increase in cellular release of the proinflammatory chemokine monocyte-chemoattractant protein 1, as compared with nontreated control astrocytes. Thus, primary human astrocytes derived from different sources can bind and internalize A beta1-42, and fetal astrocytes were more efficient in A beta1-42 uptake than adult astrocytes.
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Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Astrocitos/metabolismo , Fragmentos de Péptidos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento , Apolipoproteínas E/genética , Encéfalo/metabolismo , Células Cultivadas , Quimiocina CCL2/metabolismo , Femenino , Genotipo , Humanos , Masculino , Unión Proteica , alfa 1-Antiquimotripsina/metabolismoRESUMEN
In the Alzheimer's disease (AD) brain, binding of Clq within the Cl complex, the initiating molecule of the classical complement pathway, to apoptotic cells, DNA and amyloid-beta (Abeta), the major constituent of senile plaques, can initiate complement activation. However, the extent of activation is determined by the balance between activation and inhibition. Fluid-phase complement inhibitor C4b-binding protein (C4BP) was immunohistochemically detected in Abeta plaques and on apoptotic cells in AD brain. In vitro, C4BP bound apoptotic and necrotic but not viable brain cells (astrocytes, neurons and oligodendrocytes) and limited complement activation on dead brain cells. C4BP also bound Abeta1-42 peptide directly, via the C4BP alpha-chain, and limited the extent of complement activation by Abeta. C4BP levels in cerebrospinal fluid (CSF) of dementia patients and controls were low compared to levels in plasma and correlated with CSF levels of other inflammation-related factors. In conclusion, C4BP binds to dead brain cells and Abeta peptide in vitro, is present in CSF and possibly protects against excessive complement activation in AD brains.
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Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Apoptosis/fisiología , Proteína de Unión al Complemento C4b/fisiología , Fragmentos de Péptidos/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/patología , Secuencia de Aminoácidos , Encéfalo/metabolismo , Encéfalo/patología , Estudios de Casos y Controles , Muerte Celular , Proteína de Unión al Complemento C4b/líquido cefalorraquídeo , Proteína de Unión al Complemento C4b/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Placa Amiloide/metabolismo , Placa Amiloide/patología , Unión ProteicaRESUMEN
The Alzheimer's disease (AD) afflicted brain is neuropathologically defined by extracellular amyloid-ß (Aß) plaques and intraneuronal neurofibrillary tangles composed of hyperphosphorylated tau protein. However, accumulating evidence suggests that the presynaptic protein α-synuclein (αSyn), mainly associated with synucleinopathies like Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), is involved in the pathophysiology of AD. Lewy-related pathology (LRP), primarily comprised of αSyn, is present in a majority of autopsied AD brains, and higher levels of αSyn in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) and AD have been linked to cognitive decline. Recent studies also suggest that the asymptomatic accumulation of Aß plaques is associated with higher CSF αSyn levels in subjects at risk of sporadic AD and in individuals carrying autosomal dominant AD mutations. Experimental evidence has further linked αSyn mainly to tau hyperphosphorylation, but also to the pathological actions of Aß and the APOEε4 allele, the latter being a major genetic risk factor for both AD and DLB. In this review, we provide a summary of the current evidence proposing an involvement of αSyn either as an active or passive player in the pathophysiological ensemble of AD, and furthermore describe in detail the current knowledge of αSyn structure and inferred function.
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Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Encéfalo/metabolismo , alfa-Sinucleína/metabolismo , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/patología , Humanos , Placa Amiloide/metabolismo , Placa Amiloide/patología , Proteínas tau/metabolismoRESUMEN
The APOEÉ4 gene variant is the strongest genetic risk factor for Alzheimer's disease (AD), whereas APOEÉ3 conventionally is considered as 'risk neutral' although APOEÉ3-carriers also develop AD. Previous studies have shown that the apolipoprotein E3 (apoE3) isoform occurs as monomers, homodimers and heterodimers with apolipoprotein A-II in human body fluids and brain tissue, but the relevance of a plasma apoE3 monomer/dimer profile to AD is unknown. Here we assessed the distribution of monomers, homodimers and heterodimers in plasma from control subjects and patients with mild cognitive impairment (MCI) and AD with either a homozygous APOEÉ3 (nâ=â31 control subjects, and nâ=â14 MCI versus nâ=â5 AD patients) or APOEÉ4 genotype (nâ=â1 control subject, nâ=â21 MCI and nâ=â7 AD patients). Total plasma apoE levels were lower in APOEÉ4-carriers and overall correlated significantly to CSF Aß42, p(Thr181)-tau and t-tau levels. Apolipoprotein E dimers were only observed in the APOEÉ3-carriers and associated with total plasma apoE levels, negatively correlated to apoE monomers, but were unrelated to plasma homocysteine levels. Importantly, the APOEÉ3-carrying AD patients versus controls exhibited a significant decrease in apoE homodimers (17.8±9.6% versus 26.7±6.3%, pâ=â0.025) paralleled by an increase in apoE monomers (67.8±18.3% versus 48.5±11.2%, pâ=â0.008). In the controls, apoE monomers and heterodimers were significantly associated with plasma triglycerides; the apoE heterodimers were also associated with levels of high-density lipoprotein cholesterol. The physiological relevance of apoE dimer formation needs to be further investigated, though the distribution of apoE in monomers and dimers appears to be of relevance to AD in APOEÉ3 subjects.