Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 657
Filtrar
1.
Front Endocrinol (Lausanne) ; 15: 1374825, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38742194

RESUMO

Increasing evidence suggests that female individuals have a higher Alzheimer's disease (AD) risk associated with post-menopausal loss of circulating estradiol (E2). However, clinical data are conflicting on whether E2 lowers AD risk. One potential contributing factor is APOE. The greatest genetic risk factor for AD is APOE4, a factor that is pronounced in female individuals post-menopause. Clinical data suggests that APOE impacts the response of AD patients to E2 replacement therapy. However, whether APOE4 prevents, is neutral, or promotes any positive effects of E2 is unclear. Therefore, our goal was to determine whether APOE modulates the impact of E2 on behavior and AD pathology in vivo. To that end, mice that express human APOE3 (E3FAD) or APOE4 (E4FAD) and overproduce Aß42 were ovariectomized at either 4 months (early) or 8 months (late) and treated with vehicle or E2 for 4 months. In E3FAD mice, we found that E2 mitigated the detrimental effect of ovariectomy on memory, with no effect on Aß in the early paradigm and only improved learning in the late paradigm. Although E2 lowered Aß in E4FAD mice in the early paradigm, there was no impact on learning or memory, possibly due to higher Aß pathology compared to E3FAD mice. In the late paradigm, there was no effect on learning/memory and Aß pathology in E4FAD mice. Collectively, these data support the idea that, in the presence of Aß pathology, APOE impacts the response to E2 supplementation post-menopause.


Assuntos
Doença de Alzheimer , Apolipoproteína E3 , Apolipoproteína E4 , Estradiol , Camundongos Transgênicos , Ovariectomia , Animais , Estradiol/farmacologia , Feminino , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Camundongos , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Humanos , Comportamento Animal/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Modelos Animais de Doenças
2.
J Neuroimmune Pharmacol ; 19(1): 22, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38771543

RESUMO

SARS-CoV-2 spike proteins have been shown to cross the blood-brain barrier (BBB) in mice and affect the integrity of human BBB cell models. However, the effects of SARS-CoV-2 spike proteins in relation to sporadic, late onset, Alzheimer's disease (AD) risk have not been extensively investigated. Here we characterized the individual and combined effects of SARS-CoV-2 spike protein subunits S1 RBD, S1 and S2 on BBB cell types (induced brain endothelial-like cells (iBECs) and astrocytes (iAstrocytes)) generated from induced pluripotent stem cells (iPSCs) harboring low (APOE3 carrier) or high (APOE4 carrier) relative Alzheimer's risk. We found that treatment with spike proteins did not alter iBEC integrity, although they induced the expression of several inflammatory cytokines. iAstrocytes exhibited a robust inflammatory response to SARS-CoV-2 spike protein treatment, with differences found in the levels of cytokine secretion between spike protein-treated APOE3 and APOE4 iAstrocytes. Finally, we tested the effects of potentially anti-inflammatory drugs during SARS-CoV-2 spike protein exposure in iAstrocytes, and discovered different responses between spike protein treated APOE4 iAstrocytes and APOE3 iAstrocytes, specifically in relation to IL-6, IL-8 and CCL2 secretion. Overall, our results indicate that APOE3 and APOE4 iAstrocytes respond differently to anti-inflammatory drug treatment during SARS-CoV-2 spike protein exposure with potential implications to therapeutic responses.


Assuntos
Apolipoproteína E3 , Apolipoproteína E4 , Astrócitos , Barreira Hematoencefálica , Citocinas , Glicoproteína da Espícula de Coronavírus , Barreira Hematoencefálica/metabolismo , Humanos , Citocinas/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Astrócitos/metabolismo , Astrócitos/virologia , Astrócitos/efeitos dos fármacos , Apolipoproteína E3/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/efeitos dos fármacos , SARS-CoV-2 , COVID-19/metabolismo , COVID-19/imunologia , Células Cultivadas
3.
Nat Commun ; 15(1): 3796, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38714706

RESUMO

The metabolic implications in Alzheimer's disease (AD) remain poorly understood. Here, we conducted a metabolomics study on a moderately aging Chinese Han cohort (n = 1397; mean age 66 years). Conjugated bile acids, branch-chain amino acids (BCAAs), and glutamate-related features exhibited strong correlations with cognitive impairment, clinical stage, and brain amyloid-ß deposition (n = 421). These features demonstrated synergistic performances across clinical stages and subpopulations and enhanced the differentiation of AD stages beyond demographics and Apolipoprotein E ε4 allele (APOE-ε4). We validated their performances in eight data sets (total n = 7685) obtained from Alzheimer's Disease Neuroimaging Initiative (ADNI) and Religious Orders Study and Memory and Aging Project (ROSMAP). Importantly, identified features are linked to blood ammonia homeostasis. We further confirmed the elevated ammonia level through AD development (n = 1060). Our findings highlight AD as a metabolic disease and emphasize the metabolite-mediated ammonia disturbance in AD and its potential as a signature and therapeutic target for AD.


Assuntos
Doença de Alzheimer , Amônia , Metabolômica , Fenótipo , Humanos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Amônia/metabolismo , Idoso , Feminino , Masculino , Pessoa de Meia-Idade , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/genética , Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Ácidos e Sais Biliares/metabolismo , Idoso de 80 Anos ou mais , Estudos de Coortes
4.
Acta Neuropathol ; 147(1): 91, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38772917

RESUMO

APOEε4 is the major genetic risk factor for sporadic Alzheimer's disease (AD). Although APOEε4 is known to promote Aß pathology, recent data also support an effect of APOE polymorphism on phosphorylated Tau (pTau) pathology. To elucidate these potential effects, the pTau interactome was analyzed across APOE genotypes in the frontal cortex of 10 advanced AD cases (n = 5 APOEε3/ε3 and n = 5 APOEε4/ε4), using a combination of anti-pTau pS396/pS404 (PHF1) immunoprecipitation (IP) and mass spectrometry (MS). This proteomic approach was complemented by an analysis of anti-pTau PHF1 and anti-Aß 4G8 immunohistochemistry, performed in the frontal cortex of 21 advanced AD cases (n = 11 APOEε3/ε3 and n = 10 APOEε4/ε4). Our dataset includes 1130 and 1330 proteins enriched in IPPHF1 samples from APOEε3/ε3 and APOEε4/ε4 groups (fold change ≥ 1.50, IPPHF1 vs IPIgG ctrl). We identified 80 and 68 proteins as probable pTau interactors in APOEε3/ε3 and APOEε4/ε4 groups, respectively (SAINT score ≥ 0.80; false discovery rate (FDR) ≤ 5%). A total of 47/80 proteins were identified as more likely to interact with pTau in APOEε3/ε3 vs APOEε4/ε4 cases. Functional enrichment analyses showed that they were significantly associated with the nucleoplasm compartment and involved in RNA processing. In contrast, 35/68 proteins were identified as more likely to interact with pTau in APOEε4/ε4 vs APOEε3/ε3 cases. They were significantly associated with the synaptic compartment and involved in cellular transport. A characterization of Tau pathology in the frontal cortex showed a higher density of plaque-associated neuritic crowns, made of dystrophic axons and synapses, in APOEε4 carriers. Cerebral amyloid angiopathy was more frequent and severe in APOEε4/ε4 cases. Our study supports an influence of APOE genotype on pTau-subcellular location in AD. These results suggest a facilitation of pTau progression to Aß-affected brain regions in APOEε4 carriers, paving the way to the identification of new therapeutic targets.


Assuntos
Doença de Alzheimer , Apolipoproteína E4 , Proteínas tau , Humanos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Proteínas tau/metabolismo , Proteínas tau/genética , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Masculino , Feminino , Idoso , Fosforilação , Idoso de 80 Anos ou mais , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Proteômica , Genótipo , Pessoa de Meia-Idade
5.
Nature ; 628(8006): 154-161, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38480892

RESUMO

Several genetic risk factors for Alzheimer's disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells1. However, the relationship between lipid metabolism in glia and Alzheimer's disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer's disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer's disease having the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aß induces ACSL1 expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer's disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer's disease.


Assuntos
Doença de Alzheimer , Apolipoproteína E4 , Gotículas Lipídicas , Microglia , Animais , Feminino , Humanos , Masculino , Camundongos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Gotículas Lipídicas/metabolismo , Gotículas Lipídicas/patologia , Microglia/citologia , Microglia/metabolismo , Microglia/patologia , Triglicerídeos , Proteínas tau , Meios de Cultivo Condicionados , Fosforilação , Predisposição Genética para Doença
6.
FEBS Lett ; 598(8): 902-914, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38529702

RESUMO

Apolipoprotein E (apoE) is a regulator of lipid metabolism, cholesterol transport, and the clearance and aggregation of amyloid ß in the brain. The three human apoE isoforms apoE2, apoE3, and apoE4 only differ in one or two residues. Nevertheless, the functions highly depend on the isoform types and lipidated states. Here, we generated novel anti-apoE monoclonal antibodies (mAbs) and obtained an apoE4-selective mAb whose epitope is within residues 110-117. ELISA and bio-layer interferometry measurements demonstrated that the dissociation constants of mAbs are within the nanomolar range. Using the generated antibodies, we successfully constructed sandwich ELISA systems, which can detect all apoE isoforms or selectively detect apoE4. These results suggest the usability of the generated anti-apoE mAbs for selective detection of apoE isoforms.


Assuntos
Anticorpos Monoclonais , Apolipoproteínas E , Isoformas de Proteínas , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/química , Humanos , Isoformas de Proteínas/imunologia , Apolipoproteínas E/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/química , Apolipoproteínas E/imunologia , Animais , Epitopos/imunologia , Epitopos/química , Ensaio de Imunoadsorção Enzimática/métodos , Camundongos , Apolipoproteína E4/genética , Apolipoproteína E4/imunologia , Apolipoproteína E4/metabolismo , Camundongos Endogâmicos BALB C , Apolipoproteína E3/imunologia , Apolipoproteína E3/genética , Apolipoproteína E3/química , Apolipoproteína E3/metabolismo
7.
J Cell Mol Med ; 28(7): e18160, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38506067

RESUMO

Apolipoprotein E4 (ApoE4) is involved in the stress-response processes and is hypothesized to be a risk factor for depression by means of mitochondrial dysfunction. However, their exact roles and underlying mechanisms are largely unknown. ApoE4 transgenic mice (B6. Cg-ApoEtm1Unc Cdh18Tg( GFAP-APOE i4)1Hol /J) were subjected to stress (lipopolysaccharides, LPS) to elucidate the aetiology of ApoE4-induced depression. LPS treatment significantly aggravated depression-like behaviours, concurrent with neuroinflammation and impaired mitochondrial changes, and melatonin/Urolithin A (UA) + 5-aminoimidazole-4-carboxamide 1-ß-D-ribofuranoside (AICAR) reversed these effects in ApoE4 mice. Concurrently, ApoE4 mice exhibited mitophagy deficits, which could be further exacerbated by LPS stimulation, as demonstrated by reduced Atg5, Beclin-1 and Parkin levels, while PINK1 levels were increased. However, these changes were reversed by melatonin treatment. Additionally, proteomic profiling suggested mitochondria-related signalling and network changes in ApoE4 mice, which may underlie the exaggerated response to LPS. Furthermore, HEK 293T cells transfected with ApoE4 showed mitochondria-associated protein and mitophagy defects, including PGC-1α, TFAM, p-AMPKα, PINK1 and LC3B impairments. Additionally, it aggravates mitochondrial impairment (particularly mitophagy), which can be attenuated by triggering autophagy. Collectively, ApoE4 dysregulation enhanced depressive behaviour upon LPS stimulation.


Assuntos
Apolipoproteína E4 , Melatonina , Camundongos , Animais , Apolipoproteína E4/metabolismo , Apolipoproteína E4/farmacologia , Depressão , Melatonina/farmacologia , Melatonina/metabolismo , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/metabolismo , Proteômica , Mitocôndrias/metabolismo , Apolipoproteínas E/metabolismo , Camundongos Transgênicos , Proteínas Quinases Ativadas por AMP/metabolismo
8.
Mol Neurodegener ; 19(1): 24, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38468308

RESUMO

Microglia are highly dynamic cells that play a critical role in tissue homeostasis through the surveillance of brain parenchyma and response to cues associated with damage. Aging and APOE4 genotype are the strongest risk factors for Alzheimer's disease (AD), but how they affect microglial dynamics remains unclear. Using ex vivo confocal microscopy, we analyzed microglial dynamic behaviors in the entorhinal cortex (EC) and hippocampus CA1 of 6-, 12-, and 21-month-old mice APOE3 or APOE4 knock-in mice expressing GFP under the CX3CR1 promoter. To study microglia surveillance, we imaged microglia baseline motility for 20 min and measured the extension and retraction of processes. We found that APOE4 microglia exhibited significantly less brain surveillance (27%) compared to APOE3 microglia in 6-month-old mice; aging exacerbated this deficit. To measure microglia response to damage, we imaged process motility in response to ATP, an injury-associated signal, for 30 min. We found APOE4 microglia extended their processes significantly slower (0.9 µm/min, p < 0.005) than APOE3 microglia (1.1 µm/min) in 6-month-old animals. APOE-associated alterations in microglia motility were observed in 12- and 21-month-old animals, and this effect was exacerbated with aging in APOE4 microglia. We measured protein and mRNA levels of P2RY12, a core microglial receptor required for process movement in response to damage. We found that APOE4 microglia express significantly less P2RY12 receptors compared to APOE3 microglia despite no changes in P2RY12 transcripts. To examine if the effect of APOE4 on the microglial response to ATP also applied to amyloid ß (Aß), we infused locally Hi-Lyte Fluor 555-labeled Aß in acute brain slices of 6-month-old mice and imaged microglia movement for 2 h. APOE4 microglia showed a significantly slower (p < 0.0001) process movement toward the Aß, and less Aß coverage at early time points after Aß injection. To test whether P2RY12 is involved in process movement in response to Aß, we treated acute brain slices with a P2RY12 antagonist before Aß injection; microglial processes no longer migrated towards Aß. These results provide mechanistic insights into the impact of APOE4 genotype and aging in dynamic microglial behaviors prior to gross Aß pathology and could help explain how APOE4 brains are more susceptible to AD pathogenesis.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Animais , Camundongos , Trifosfato de Adenosina/metabolismo , Trifosfato de Adenosina/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Encéfalo/metabolismo , Genótipo , Camundongos Transgênicos , Microglia/metabolismo
9.
J Alzheimers Dis ; 97(4): 1629-1639, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38306049

RESUMO

APOE2 lowers Alzheimer's disease (AD) risk; unfortunately, the mechanism remains poorly understood and the use of mice models is problematic as APOE2 homozygosity is associated with hyperlipidemia. In this study, we developed mice that are heterozygous for APOE2 and APOE3 or APOE4 and overexpress amyloid-ß peptide (Aß) (EFAD) to evaluate the effect of APOE2 dosage on Aß pathology. We found that heterozygous mice do not exhibit hyperlipidemia. Hippocampal but not cortical levels of soluble Aß42 followed the order E2/2FAD > E2/3FAD≤E3/3FAD and E2/2FAD > E2/4FAD < E4/4FAD without an effect on insoluble Aß42. These findings offer initial insights on the impact of APOE2 on Aß pathology.


Assuntos
Doença de Alzheimer , Hiperlipidemias , Camundongos , Animais , Apolipoproteína E2/genética , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Camundongos Transgênicos , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4/metabolismo , Apolipoproteína E3 , Camundongos Endogâmicos , Hipocampo/patologia , Hiperlipidemias/genética
10.
Exp Neurol ; 374: 114702, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38301863

RESUMO

Repetitive mild traumatic brain injuries (r-mTBI) sustained in the military or contact sports have been associated with the accumulation of extracellular tau in the brain, which may contribute to the pathogenesis of neurodegenerative tauopathies. The expression of the apolipoprotein E4 (apoE4) isoform has been associated with higher levels of tau in the brain, and worse clinical outcomes after r-mTBI, though the influence of apoE genotype on extracellular tau dynamics in the brain is poorly understood. We recently demonstrated that extracellular tau can be eliminated across blood-brain barrier (BBB), which is progressively impaired following r-mTBI. The current studies investigated the influence of repetitive mild TBI (r-mTBI) and apoE genotype on the elimination of extracellular solutes from the brain. Following intracortical injection of biotin-labeled tau into humanized apoE-Tr mice, the levels of exogenous tau residing in the brain of apoE4 mice were elevated compared to other isoforms, indicating reduced tau elimination. Additionally, we found exposure to r-mTBI increased tau residence in apoE2 mice, similar to our observations in E2FAD animals. Each of these findings may be the result of diminished tau efflux via LRP1 at the BBB, as LRP1 inhibition significantly reduced tau uptake in endothelial cells and decreased tau transit across an in vitro model of the BBB (basolateral-to-apical). Notably, we showed that injury and apoE status, (particularly apoE4) resulted in chronic alterations in BBB integrity, pericyte coverage, and AQP4 polarization. These aberrations coincided with an atypical reactive astrocytic gene signature indicative of diminished CSF-ISF exchange. Our work found that CSF movement was reduced in the chronic phase following r-mTBI (>18 months post injury) across all apoE genotypes. In summary, we show that apoE genotype strongly influences cerebrovascular homeostasis, which can lead to age-dependent deficiencies in the elimination of toxic proteins from the brain, like tau, particularly in the aftermath of head trauma.


Assuntos
Apolipoproteína E4 , Concussão Encefálica , Camundongos , Animais , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Camundongos Transgênicos , Células Endoteliais/metabolismo , Encéfalo/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Concussão Encefálica/metabolismo
11.
Food Funct ; 15(4): 2249-2264, 2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38319599

RESUMO

The ApoE4 allele is the strongest genetic determinant for Alzheimer's disease (AD), while obesity is a strong environmental risk for AD. The modulatory effect of the ApoE genotype on aging-related cognitive function in tandem with a high-fat diet (HFD) remains uncertain. This study aimed to elucidate the effects of ApoE3/ApoE4 genotypes in aged mice exposed to a HFD, and the benefits of n-3 polyunsaturated fatty acids (PUFAs) from fish oil. Remarkably, the HFD led to weight gain and lipid accumulation, more pronounced in ApoE3 mice, while ApoE4 mice experienced exacerbated cerebral insulin resistance, neuroinflammation, and oxidative stress. Critically, n-3 PUFAs modulated the cerebral insulin signaling via the IRS-1/AKT/GLUT4 pathway, mitigated microglial hyperactivity, and reduced IL-6 and MDA levels, thereby counteracting cognitive deficits. These findings highlight the contrasting impacts of ApoE genotypes on aging mice exposed to a HFD, supporting n-3 PUFAs as a strategic nutritional intervention for brain health, especially for ApoE4 carriers.


Assuntos
Doença de Alzheimer , Ácidos Graxos Ômega-3 , Camundongos , Animais , Dieta Hiperlipídica/efeitos adversos , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Apolipoproteína E3/genética , Apolipoproteínas E/genética , Genótipo , Cognição , Doença de Alzheimer/genética , Doença de Alzheimer/prevenção & controle , Doença de Alzheimer/metabolismo , Envelhecimento , Camundongos Transgênicos
12.
J Alzheimers Dis ; 97(3): 1007-1031, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38306054

RESUMO

Apolipoprotein E4 (APOE4), although yet-to-be fully understood, increases the risk and lowers the age of onset of Alzheimer's disease (AD), which is the major cause of dementia among elderly individuals. The endosome-lysosome and autophagy pathways, which are necessary for homeostasis in both neurons and glia, are dysregulated even in early AD. Nonetheless, the contributory roles of these pathways to developing AD-related pathologies in APOE4 individuals and models are unclear. Therefore, this review summarizes the dysregulations in the endosome-lysosome and autophagy pathways in APOE4 individuals and non-human models, and how these anomalies contribute to developing AD-relevant pathologies. The available literature suggests that APOE4 causes endosomal enlargement, increases endosomal acidification, impairs endosomal recycling, and downregulates exosome production. APOE4 impairs autophagy initiation and inhibits basal autophagy and autophagy flux. APOE4 promotes lysosome formation and trafficking and causes ApoE to accumulate in lysosomes. APOE4-mediated changes in the endosome, autophagosome and lysosome could promote AD-related features including Aß accumulation, tau hyperphosphorylation, glial dysfunction, lipid dyshomeostasis, and synaptic defects. ApoE4 protein could mediate APOE4-mediated endosome-lysosome-autophagy changes. ApoE4 impairs vesicle recycling and endosome trafficking, impairs the synthesis of autophagy genes, resists being dissociated from its receptors and degradation, and forms a stable folding intermediate that could disrupt lysosome structure. Drugs such as molecular correctors that target ApoE4 molecular structure and enhance autophagy may ameliorate the endosome-lysosome-autophagy-mediated increase in AD risk in APOE4 individuals.


Assuntos
Doença de Alzheimer , Humanos , Idoso , Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Alelos , Endossomos/metabolismo , Lisossomos/metabolismo , Autofagia/genética
13.
J Cell Biol ; 223(4)2024 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-38334983

RESUMO

The E4 variant of APOE strongly predisposes individuals to late-onset Alzheimer's disease. We demonstrate that in response to lipogenesis, apolipoprotein E (APOE) in astrocytes can avoid translocation into the endoplasmic reticulum (ER) lumen and traffic to lipid droplets (LDs) via membrane bridges at ER-LD contacts. APOE knockdown promotes fewer, larger LDs after a fatty acid pulse, which contain more unsaturated triglyceride after fatty acid pulse-chase. This LD size phenotype was rescued by chimeric APOE that targets only LDs. Like APOE depletion, APOE4-expressing astrocytes form a small number of large LDs enriched in unsaturated triglyceride. Additionally, the LDs in APOE4 cells exhibit impaired turnover and increased sensitivity to lipid peroxidation. Our data indicate that APOE plays a previously unrecognized role as an LD surface protein that regulates LD size and composition. APOE4 causes aberrant LD composition and morphology. Our study contributes to accumulating evidence that APOE4 astrocytes with large, unsaturated LDs are sensitized to lipid peroxidation, which could contribute to Alzheimer's disease risk.


Assuntos
Doença de Alzheimer , Apolipoproteínas E , Astrócitos , Gotículas Lipídicas , Triglicerídeos , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Astrócitos/metabolismo , Ácidos Graxos/metabolismo , Gotículas Lipídicas/metabolismo , Triglicerídeos/metabolismo
14.
Neuron ; 112(7): 1100-1109.e5, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38266643

RESUMO

The Apolipoprotein E gene (APOE) is of great interest due to its role as a risk factor for late-onset Alzheimer's disease. ApoE is secreted by astrocytes in the central nervous system in high-density lipoprotein (HDL)-like lipoproteins. Structural models of lipidated ApoE of high resolution could aid in a mechanistic understanding of how ApoE functions in health and disease. Using monoclonal Fab and F(ab')2 fragments, we characterize the structure of lipidated ApoE on astrocyte-secreted lipoproteins. Our results provide support for the "double-belt" model of ApoE in nascent discoidal HDL-like lipoproteins, where two ApoE proteins wrap around the nanodisc in an antiparallel conformation. We further show that lipidated, recombinant ApoE accurately models astrocyte-secreted ApoE lipoproteins. Cryogenic electron microscopy of recombinant lipidated ApoE further supports ApoE adopting antiparallel dimers in nascent discoidal lipoproteins.


Assuntos
Apolipoproteínas E , Astrócitos , Lipoproteínas , Astrócitos/metabolismo , Apolipoproteínas E/genética , Lipoproteínas HDL/química , Lipoproteínas HDL/metabolismo , Sistema Nervoso Central/metabolismo , Apolipoproteína E4/metabolismo , Apolipoproteína E3/metabolismo
15.
Alzheimers Res Ther ; 16(1): 7, 2024 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-38212861

RESUMO

BACKGROUND: APOE4 is the strongest genetic risk factor for sporadic Alzheimer's disease (AD), whereas APOE2 confers protection. However, effects of APOE on neurodegeneration in cognitively intact individuals, and how these associations evolve with cognitive decline, are unclear. Furthermore, few studies have evaluated whether effects of APOE on neurodegenerative changes are modified by other AD key risk factors including age and sex. METHODS: Participants included older adults (57% women; 77 ± 7 years) from the Rancho Bernardo Study of Health Aging and the University of California San Diego Alzheimer's Disease Research Center, including 192 cognitively normal (CN) individuals and 33 with mild cognitive impairment. Participants underwent diffusion MRI, and multicompartment restriction spectrum imaging (RSI) metrics were computed in white matter, gray matter, and subcortical regions of interest. Participants were classified as APOE4 carriers, APOE2 carriers, and APOE3 homozygotes. Analysis of covariance among CN (adjusting for age, sex, and scanner) assessed differences in brain microstructure by APOE, as well as interactions between APOE and sex. Analyses across all participants examined interactions between APOE4 and cognitive status. Linear regressions assessed APOE by age interactions. RESULTS: Among CN, APOE4 carriers showed lower entorhinal cortex neurite density than non-carriers, whereas APOE2 carriers showed lower cingulum neurite density than non-carriers. Differences in entorhinal microstructure by APOE4 and in entorhinal and cingulum microstructure by APOE2 were present for women only. Age correlated with lower entorhinal restricted isotropic diffusion among APOE4 non-carriers, whereas age correlated with lower putamen restricted isotropic diffusion among APOE4 carriers. Differences in microstructure between cognitively normal and impaired participants were stronger for APOE4-carriers in medial temporal regions, thalamus, and global gray matter, but stronger for non-carriers in caudate. CONCLUSIONS: The entorhinal cortex may be an early target of neurodegenerative changes associated with APOE4 in presymptomatic individuals, whereas APOE2 may support beneficial white matter and entorhinal microstructure, with potential sex differences that warrant further investigation. APOE modifies microstructural patterns associated with aging and cognitive impairment, which may advance the development of biomarkers to distinguish microstructural changes characteristic of normal brain aging, APOE-dependent pathways, and non-AD etiologies.


Assuntos
Doença de Alzheimer , Apolipoproteína E2 , Apolipoproteína E4 , Disfunção Cognitiva , Idoso , Feminino , Humanos , Masculino , Doença de Alzheimer/genética , Apolipoproteína E2/genética , Apolipoproteína E2/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Cognição , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Idoso de 80 Anos ou mais
16.
Exp Brain Res ; 242(3): 543-557, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38206365

RESUMO

Apolipoprotein E ε4 allele (APOE4) is the predominant genetic risk factor for late-onset Alzheimer's disease (AD). APOE4 mouse models have provided advances in the understanding of disease pathogenesis, but unaccounted variables like rodent housing status may hinder translational outcomes. Non-sterile aspects like food and bedding can be major sources of changes in rodent microflora. Alterations in intestinal microbial ecology can cause mucosal barrier impairment and increase pro-inflammatory signals. The present study examined the role of sterile and non-sterile food and housing on redox indicators and the immune status of humanized-APOE4 knock-in mice (hAPOe4). hAPOE4 mice were housed under sterile conditions until 22 months of age, followed by the transfer of a cohort of mice to non-sterile housing for 2 months. At 24 months of age, the redox/immunologic status was evaluated by flow cytometry/ELISA. hAPOE4 females housed under non-sterile conditions exhibited: (1) higher neuronal and microglial oxygen radical production and (2) lower CD68+ microglia (brain) and CD8+ T cells (periphery) compared to sterile-housed mice. In contrast, hAPOE4 males in non-sterile housing exhibited: (1) higher MHCII+ microglia and CD11b+CD4+ T cells (brain) and (2) higher CD11b+CD4+ T cells and levels of lipopolysaccharide-binding protein and inflammatory cytokines in the periphery relative to sterile-housed mice. This study demonstrated that sterile vs. non-sterile housing conditions are associated with the activation of redox and immune responses in the brain and periphery in a sex-dependent manner. Therefore, housing status may contribute to variable outcomes in both the brain and periphery.


Assuntos
Doença de Alzheimer , Apolipoproteína E4 , Humanos , Camundongos , Animais , Feminino , Masculino , Idoso , Lactente , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Microglia/patologia , Doença de Alzheimer/genética , Qualidade Habitacional , Caracteres Sexuais , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Encéfalo/metabolismo , Sistema Imunitário/metabolismo , Sistema Imunitário/patologia , Camundongos Transgênicos
17.
Nat Rev Neurosci ; 25(2): 91-110, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38191720

RESUMO

The ɛ4 allele of the apolipoprotein E gene (APOE), which translates to the APOE4 isoform, is the strongest genetic risk factor for late-onset Alzheimer disease (AD). Within the CNS, APOE is produced by a variety of cell types under different conditions, posing a challenge for studying its roles in AD pathogenesis. However, through powerful advances in research tools and the use of novel cell culture and animal models, researchers have recently begun to study the roles of APOE4 in AD in a cell type-specific manner and at a deeper and more mechanistic level than ever before. In particular, cutting-edge omics studies have enabled APOE4 to be studied at the single-cell level and have allowed the identification of critical APOE4 effects in AD-vulnerable cellular subtypes. Through these studies, it has become evident that APOE4 produced in various types of CNS cell - including astrocytes, neurons, microglia, oligodendrocytes and vascular cells - has diverse roles in AD pathogenesis. Here, we review these scientific advances and propose a cell type-specific APOE4 cascade model of AD. In this model, neuronal APOE4 emerges as a crucial pathological initiator and driver of AD pathogenesis, instigating glial responses and, ultimately, neurodegeneration. In addition, we provide perspectives on future directions for APOE4 research and related therapeutic developments in the context of AD.


Assuntos
Doença de Alzheimer , Animais , Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Neurônios/metabolismo , Neuroglia/metabolismo , Astrócitos/metabolismo
18.
J Neuroinflammation ; 21(1): 1, 2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-38178204

RESUMO

BACKGROUND: Late-onset Alzheimer's disease (LOAD) is the most common form of dementia; it disproportionally affects women in terms of both incidence rates and severity of progression. The cellular and molecular mechanisms underlying this clinical phenomenon remain elusive and ill-defined. METHODS: In-depth analyses were performed with multiple human LOAD single-nucleus transcriptome datasets to thoroughly characterize cell populations in the cerebral cortex. ROSMAP bulk human brain tissue transcriptome and DNA methylome datasets were also included for validation. Detailed assessments of microglial cell subpopulations and their relevance to sex-biased changes at the tissue level were performed. Clinical trait associations, cell evolutionary trajectories, and transcription regulon analyses were conducted. RESULTS: The relative numbers of functionally defective microglia were aberrantly increased uniquely among affected females. Substratification of the microglia into different subtypes according to their transcriptomic signatures identified a group of female-enriched and disease-associated microglia (FDAMic), the numbers of which were positively associated with disease severity. Phenotypically, these cells exhibit transcriptomic signatures that support active proliferation, MHC class II autoantigen presentation and amyloid-ß binding, but they are also likely defective in phagocytosis. FDAMic are likely evolved from female activated response microglia (ARMic) with an APOE4 background and compromised estrogen receptor (ER) signaling that is deemed to be active among most subtypes of microglia. CONCLUSION: This study offered important insights at both the cellular and molecular levels into how ER signaling affects microglial heterogeneity and function. FDAMic are associated with more advanced pathologies and severe trends of cognitive decline. Their emergence could, at least in part, explain the phenomenon of greater penetrance of the APOE4 genotype found in females. The biases of FDAMic emergence toward female sex and APOE4 status may also explain why hormone replacement therapy is more effective in APOE4 carriers. The pathologic nature of FDAMic suggests that selective modulations of these cells may help to regain brain neuroimmune homeostasis, serving as a new target for future drug development.


Assuntos
Doença de Alzheimer , Humanos , Feminino , Doença de Alzheimer/patologia , Microglia/metabolismo , Caracteres Sexuais , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Encéfalo/metabolismo
19.
J Alzheimers Dis ; 97(2): 753-775, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38217595

RESUMO

BACKGROUND: Apolipoprotein E4 (APOE4) is the most prevalent genetic risk factor of Alzheimer's disease. Several studies suggest that APOE4 binding to its receptors is associated with their internalization and accumulation in intracellular compartments. Importantly, this phenomenon also occurs with other, non-ApoE receptors. Based on these observations, we hypothesized that APOE4 pathological effects are mediated by impairment in the life cycle of distinct receptors (APOER2, LRP1, IR, VEGFR). OBJECTIVE: To examine the effects of APOE genotype on receptors protein levels and compartmentalization. METHODS: Primary mouse neurons were prepared from APOE3 or APOE4 targeted replacement mice, or APOE-KO mice. Specific receptors protein levels were evaluated in these neurons, utilizing immunofluorescent staining. Additionally, surface membrane protein levels of those receptors were assessed by cell surface biotinylation assay and ELISA. Receptors' colocalization with intracellular compartments was assessed by double staining and confocal microscopy, followed by colocalization analysis. Finally, LRP1 or APOER2 were knocked-down with CRISPR/Cas9 system to examine their role in mediating APOE4 effects on the receptors. RESULTS: Our results revealed lower receptors' levels in APOE4, specifically on the membrane surface. Additionally, APOE4 affects the compartmentation of these receptors in two patterns: the first was observed with LRP1 and was associated with decreased receptor levels in numerous intracellular compartments. The second was obtained with the other receptors and was associated with their accumulation in early endosomes and their decrease in the late endosomes. CONCLUSIONS: These results provide a unifying mechanism, in which APOE4 drives the down regulation of various receptors, which plays important roles in distinct APOE4 related pathological processes.


Assuntos
Doença de Alzheimer , Camundongos , Animais , Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Camundongos Transgênicos , Apolipoproteínas E , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo
20.
FEBS Lett ; 598(3): 347-362, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38279679

RESUMO

The low-density lipoprotein (LDL) receptor-related protein (LRP)1 participates in the metabolism of apolipoprotein (apo) E-containing lipoproteins (apoE-LP). We investigated the effects of modifications of cysteine (Cys)-thiol of apoE on LRP1-mediated metabolism. Among the three isoforms, apoE2-LP exhibited the lowest affinity for LRP1 but was significantly catabolized, whereas apoE4-LP was sufficiently bound to LRP1 but showed the lowest catabolic capability. The reduction enhanced the binding and suppressed the catabolism of apoE3-LP, but had no effect on apoE2-LP. The formation of disulfide-linked complexes with apoAII suppressed binding, but enhanced the catabolism of apoE2-LP. Redox modifications of apoE-Cys-thiol may modulate the LRP1-mediated metabolism of apoE2- or apoE3-LP, but not apoE4-LP. The failure of this function may be involved in the pathophysiology of dyslipidemia.


Assuntos
Apolipoproteínas E , Compostos de Sulfidrila , Apolipoproteína E2/metabolismo , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Apolipoproteínas E/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Triglicerídeos/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas de Transporte
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA