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1.
Commun Biol ; 4(1): 61, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420340

RESUMO

Alzheimer's Disease (AD) is a devastating neurodegenerative disorder without a cure. Here we show that mitochondrial respiratory chain complex I is an important small molecule druggable target in AD. Partial inhibition of complex I triggers the AMP-activated protein kinase-dependent signaling network leading to neuroprotection in symptomatic APP/PS1 female mice, a translational model of AD. Treatment of symptomatic APP/PS1 mice with complex I inhibitor improved energy homeostasis, synaptic activity, long-term potentiation, dendritic spine maturation, cognitive function and proteostasis, and reduced oxidative stress and inflammation in brain and periphery, ultimately blocking the ongoing neurodegeneration. Therapeutic efficacy in vivo was monitored using translational biomarkers FDG-PET, 31P NMR, and metabolomics. Cross-validation of the mouse and the human transcriptomic data from the NIH Accelerating Medicines Partnership-AD database demonstrated that pathways improved by the treatment in APP/PS1 mice, including the immune system response and neurotransmission, represent mechanisms essential for therapeutic efficacy in AD patients.

2.
Neuron ; 109(3): 438-447.e6, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33321072

RESUMO

The ε4 allele of the apolipoprotein E gene (APOE4) is a strong genetic risk factor for Alzheimer's disease (AD) and multiple vascular conditions. ApoE is abundantly expressed in multiple brain cell types, including astrocytes, microglia, and vascular mural cells (VMCs). Here, we show that VMC-specific expression of apoE4 in mice impairs behavior and cerebrovascular function. Expression of either apoE3 or apoE4 in VMCs was sufficient to rescue the hypercholesterolemia and atherosclerosis phenotypes seen in Apoe knockout mice. Intriguingly, vascular expression of apoE4, but not apoE3, reduced arteriole blood flow, impaired spatial learning, and increased anxiety-like phenotypes. Single-cell RNA sequencing of vascular and glial cells revealed that apoE4 in VMCs was associated with astrocyte activation, while apoE3 was linked to angiogenic signature in pericytes. Together, our data support cell-autonomous effects of vascular apoE on brain homeostasis in an isoform-dependent manner, suggesting a critical contribution of vascular apoE to AD pathogenesis.


Assuntos
Apolipoproteína E4/genética , Arteríolas/metabolismo , Astrócitos/metabolismo , Encéfalo/metabolismo , Gliose/genética , Animais , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Apolipoproteína E4/metabolismo , Arteríolas/patologia , Astrócitos/patologia , Encéfalo/patologia , Gliose/metabolismo , Gliose/patologia , Camundongos , Camundongos Transgênicos
3.
Nat Commun ; 11(1): 5540, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33139712

RESUMO

APOE4 is the strongest genetic risk factor associated with late-onset Alzheimer's disease (AD). To address the underlying mechanism, we develop cerebral organoid models using induced pluripotent stem cells (iPSCs) with APOE ε3/ε3 or ε4/ε4 genotype from individuals with either normal cognition or AD dementia. Cerebral organoids from AD patients carrying APOE ε4/ε4 show greater apoptosis and decreased synaptic integrity. While AD patient-derived cerebral organoids have increased levels of Aß and phosphorylated tau compared to healthy subject-derived cerebral organoids, APOE4 exacerbates tau pathology in both healthy subject-derived and AD patient-derived organoids. Transcriptomics analysis by RNA-sequencing reveals that cerebral organoids from AD patients are associated with an enhancement of stress granules and disrupted RNA metabolism. Importantly, isogenic conversion of APOE4 to APOE3 attenuates the APOE4-related phenotypes in cerebral organoids from AD patients. Together, our study using human iPSC-organoids recapitulates APOE4-related phenotypes and suggests APOE4-related degenerative pathways contributing to AD pathogenesis.


Assuntos
Doença de Alzheimer/metabolismo , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Organoides/metabolismo , Sinapses/metabolismo , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Regulação da Expressão Gênica , Genótipo , Humanos , Organoides/patologia , RNA/metabolismo , Transcriptoma
4.
Alzheimers Dement ; 16(10): 1372-1383, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32827351

RESUMO

INTRODUCTION: Cerebrovascular pathologies including cerebral amyloid angiopathy (CAA) and blood-brain barrier (BBB) dysregulation are prominent features in the majority of Alzheimer's disease (AD) cases. METHODS: We performed neuropathologic and biochemical studies on a large, neuropathologically confirmed human AD cohort (N = 469). Amounts of endothelial tight junction proteins claudin-5 (CLDN5) and occludin (OCLN), and major AD-related molecules (amyloid beta [Aß40], Aß42, tau, p-tau, and apolipoprotein E) in the temporal cortex were assessed by ELISA. RESULTS: Higher levels of soluble tau, insoluble p-tau, and apolipoprotein E (apoE) were independently correlated with lower levels of endothelial tight junction proteins CLDN5 and OCLN in AD brains. Although high Aß40 levels, APOE ε4, and male sex were predominantly associated with exacerbated CAA severity, those factors did not influence tight junction protein levels. DISCUSSION: Refining the molecular mechanisms connecting tau, Aß, and apoE with cerebrovascular pathologies is critical for greater understanding of AD pathogenesis and establishing effective therapeutic interventions for the disease.

5.
Neuron ; 106(5): 727-742.e6, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32199103

RESUMO

Evidence suggests interplay among the three major risk factors for Alzheimer's disease (AD): age, APOE genotype, and sex. Here, we present comprehensive datasets and analyses of brain transcriptomes and blood metabolomes from human apoE2-, apoE3-, and apoE4-targeted replacement mice across young, middle, and old ages with both sexes. We found that age had the greatest impact on brain transcriptomes highlighted by an immune module led by Trem2 and Tyrobp, whereas APOE4 was associated with upregulation of multiple Serpina3 genes. Importantly, these networks and gene expression changes were mostly conserved in human brains. Finally, we observed a significant interaction between age, APOE genotype, and sex on unfolded protein response pathway. In the periphery, APOE2 drove distinct blood metabolome profile highlighted by the upregulation of lipid metabolites. Our work identifies unique and interactive molecular pathways underlying AD risk factors providing valuable resources for discovery and validation research in model systems and humans.


Assuntos
Envelhecimento/genética , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Encéfalo/metabolismo , Serpinas/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Fatores Etários , Doença de Alzheimer/metabolismo , Animais , Apolipoproteína E2/genética , Apolipoproteína E3/genética , Apolipoproteína E4/genética , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Genótipo , Humanos , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Metaboloma , Camundongos , Camundongos Transgênicos , Fatores de Proteção , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Fatores de Risco , Fatores Sexuais , Resposta a Proteínas não Dobradas/genética
6.
Arterioscler Thromb Vasc Biol ; 40(1): 128-144, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31665905

RESUMO

OBJECTIVE: The ε4 allele of the APOE gene (APOE4) is the strongest genetic risk factor for Alzheimer disease when compared with the common ε3 allele. Although there has been significant progress in understanding how apoE4 (apolipoprotein E4) drives amyloid pathology, its effects on amyloid-independent pathways, in particular cerebrovascular integrity and function, are less clear. Approach and Results: Here, we show that brain pericytes, the mural cells of the capillary walls, differentially modulate endothelial cell phenotype in an apoE isoform-dependent manner. Extracellular matrix protein induction, tube-like structure formation, and barrier formation were lower with endothelial cells cocultured with pericytes isolated from apoE4-targeted replacement (TR) mice compared with those from apoE3-TR mice. Importantly, aged apoE4-targeted replacement mice had decreased extracellular matrix protein expression and increased plasma protein leakages compared with apoE3-TR mice. CONCLUSIONS: ApoE4 impairs pericyte-mediated basement membrane formation, potentially contributing to the cerebrovascular effects of apoE4.


Assuntos
Doença de Alzheimer/genética , Apolipoproteínas E/genética , Membrana Basal/metabolismo , Encéfalo/metabolismo , Endotélio Vascular/metabolismo , Regulação da Expressão Gênica , Pericitos/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Apolipoproteínas E/biossíntese , Membrana Basal/patologia , Encéfalo/patologia , Células Cultivadas , Modelos Animais de Doenças , Endotélio Vascular/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pericitos/patologia , Isoformas de Proteínas
7.
Proc Natl Acad Sci U S A ; 116(47): 23790-23796, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31690660

RESUMO

Carrying premature termination codons in 1 allele of the ABCA7 gene is associated with an increased risk for Alzheimer's disease (AD). While the primary function of ABCA7 is to regulate the transport of phospholipids and cholesterol, ABCA7 is also involved in maintaining homeostasis of the immune system. Since inflammatory pathways causatively or consequently participate in AD pathogenesis, we studied the effects of Abca7 haplodeficiency in mice on brain immune responses under acute and chronic conditions. When acute inflammation was induced through peripheral lipopolysaccharide injection in control or heterozygous Abca7 knockout mice, partial ABCA7 deficiency diminished proinflammatory responses by impairing CD14 expression in the brain. On breeding to App NL-G-F knockin mice, we observed increased amyloid-ß (Aß) accumulation and abnormal endosomal morphology in microglia. Taken together, our results demonstrate that ABCA7 loss of function may contribute to AD pathogenesis by altering proper microglial responses to acute inflammatory challenges and during the development of amyloid pathology, providing insight into disease mechanisms and possible treatment strategies.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Encéfalo/imunologia , Haploinsuficiência , Microglia/imunologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Perfilação da Expressão Gênica , Imunidade Inata/genética , Camundongos , Camundongos Transgênicos , Transcriptoma
8.
Nat Rev Neurol ; 15(9): 501-518, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31367008

RESUMO

Polymorphism in the apolipoprotein E (APOE) gene is a major genetic risk determinant of late-onset Alzheimer disease (AD), with the APOE*ε4 allele conferring an increased risk and the APOE*ε2 allele conferring a decreased risk relative to the common APOE*ε3 allele. Strong evidence from clinical and basic research suggests that a major pathway by which APOE4 increases the risk of AD is by driving earlier and more abundant amyloid pathology in the brains of APOE*ε4 carriers. The number of amyloid-ß (Aß)-dependent and Aß-independent pathways that are known to be differentially modulated by APOE isoforms is increasing. For example, evidence is accumulating that APOE influences tau pathology, tau-mediated neurodegeneration and microglial responses to AD-related pathologies. In addition, APOE4 is either pathogenic or shows reduced efficiency in multiple brain homeostatic pathways, including lipid transport, synaptic integrity and plasticity, glucose metabolism and cerebrovascular function. Here, we review the recent progress in clinical and basic research into the role of APOE in AD pathogenesis. We also discuss how APOE can be targeted for AD therapy using a precision medicine approach.


Assuntos
Doença de Alzheimer , Apolipoproteínas E/genética , Encéfalo/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/metabolismo , Predisposição Genética para Doença , Humanos , Placa Amiloide/patologia , Polimorfismo Genético
10.
Brain ; 142(4): 1077-1092, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30770921

RESUMO

While the accumulation and aggregation of amyloid-ß and tau are central events in the pathogenesis of Alzheimer's disease, there is increasing evidence that cerebrovascular pathology is also abundant in Alzheimer's disease brains. In brain capillaries, endothelial cells are connected closely with one another through transmembrane tight junction proteins forming the blood-brain barrier. Because the blood-brain barrier tightly regulates the exchange of molecules between brain and blood and maintains brain homeostasis, its impairment is increasingly recognized as a critical factor contributing to Alzheimer's disease pathogenesis. However, the pathological relationship between blood-brain barrier properties and Alzheimer's disease progression in the human brain is not fully understood. In this study, we show that the loss of cortical tight junction proteins is a common event in Alzheimer's disease, and is correlated with synaptic degeneration. By quantifying the amounts of major tight junction proteins, claudin-5 and occludin, in 12 brain regions dissected from post-mortem brains of normal ageing (n = 10), pathological ageing (n = 14) and Alzheimer's disease patients (n = 19), we found that they were selectively decreased in cortical areas in Alzheimer's disease. Cortical tight junction proteins were decreased in association with the Braak neurofibrillary tangle stage. There was also a negative correlation between the amount of tight junction proteins and the amounts of insoluble Alzheimer's disease-related proteins, in particular amyloid-ß40, in cortical areas. In addition, the amount of tight junction proteins in these areas correlated positively with those of synaptic markers. Thus, loss of cortical tight junction proteins in Alzheimer's disease is associated with insoluble amyloid-ß40 and loss of synaptic markers. Importantly, the positive correlation between claudin-5 and synaptic markers, in particular synaptophysin, was present independent of insoluble amyloid-ß40, amyloid-ß42 and tau values, suggesting that loss of cortical tight junction proteins and synaptic degeneration is present, at least in part, independent of insoluble Alzheimer's disease-related proteins. Collectively, these results indicate that loss of tight junction proteins occurs predominantly in the neocortex during Alzheimer's disease progression. Further, our findings provide a neuropathological clue as to how endothelial tight junction pathology may contribute to Alzheimer's disease pathogenesis in both synergistic and additive manners to typical amyloid-ß and tau pathologies.


Assuntos
Doença de Alzheimer/fisiopatologia , Barreira Hematoencefálica/fisiologia , Proteínas de Junções Íntimas/fisiologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/patologia , Progressão da Doença , Células Endoteliais/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neocórtex/patologia , Emaranhados Neurofibrilares/patologia , Fragmentos de Peptídeos/metabolismo , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/metabolismo , Junções Íntimas/fisiologia , Proteínas tau/metabolismo
11.
J Clin Invest ; 129(3): 1272-1277, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30741718

RESUMO

Carrying the ε4 allele of the APOE gene encoding apolipoprotein E (APOE4) markedly increases the risk for late-onset Alzheimer's disease (AD), in which APOE4 exacerbates the brain accumulation and subsequent deposition of amyloid-ß (Aß) peptides. While the LDL receptor-related protein 1 (LRP1) is a major apoE receptor in the brain, we found that its levels are associated with those of insoluble Aß depending on APOE genotype status in postmortem AD brains. Thus, to determine the functional interaction of apoE4 and LRP1 in brain Aß metabolism, we crossed neuronal LRP1-knockout mice with amyloid model APP/PS1 mice and APOE3-targeted replacement (APO3-TR) or APOE4-TR mice. Consistent with previous findings, mice expressing apoE4 had increased Aß deposition and insoluble amounts of Aß40 and Aß42 in the hippocampus of APP/PS1 mice compared with those expressing apoE3. Intriguingly, such effects were reversed in the absence of neuronal LRP1. Neuronal LRP1 deficiency also increased detergent-soluble apoE4 levels, which may contribute to the inhibition of Aß deposition. Together, our results suggest that apoE4 exacerbates Aß pathology through a mechanism that depends on neuronal LRP1. A better understanding of apoE isoform-specific interaction with their metabolic receptor LRP1 on Aß metabolism is crucial for defining APOE4-related risk for AD.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4/metabolismo , Hipocampo/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Fragmentos de Peptídeos/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Animais , Apolipoproteína E4/genética , Modelos Animais de Doenças , Hipocampo/patologia , Humanos , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Camundongos , Camundongos Knockout para ApoE , Fragmentos de Peptídeos/genética
12.
Exp Neurol ; 300: 13-21, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29106980

RESUMO

Pericytes are a major component of cerebrovasculature playing a key role in maintaining cerebrovascular homeostasis. These cells have also been suggested to regulate brain metabolism of amyloid-ß (Aß), disturbances of which are believed to contribute to the pathogenesis of Alzheimer's disease (AD). To examine the effects of pericytes on brain Aß metabolism, C3H/10T1/2 mouse mesenchymal stem cells were differentiated into pericytes and stereotaxically injected into the brains of amyloid AD model APP/PS1 mice at the age of 18 to 20months. Consistent with a role of pericytes in modulating cerebrovascular function, brain microcirculation in the pericyte-injected hemisphere of the mice was increased 3weeks after implantation compared to the contralateral hemisphere when measured by laser speckle contrast analysis technology. Importantly, enzyme-linked immunosorbent assay revealed that the levels of insoluble Aß40 and Aß42 were significantly lower in the hippocampus of the pericyte-injected hemisphere of the APP/PS1 mice than that of the contralateral side. Consistently, immunohistochemical analysis demonstrated that the pericyte implantation reduced Aß deposition in the hippocampus. When brain slices from the APP/PS1 mice were incubated with C3H/10T1/2 cell-derived pericytes, Aß42 levels were significantly reduced in a manner that depends on the expression of a major Aß endocytic receptor, the low-density lipoprotein receptor-related protein 1 (LRP1). While LRP1 mediated the cellular uptake of Aß in the pericytes, the amounts of major Aß-degrading enzymes were not affected by LRP1 knockdown. Together, our findings indicate that mesenchymal stem cell-derived pericytes have the capacity to reduce brain Aß and related pathology, and suggest that cell-based therapy through transplantation of pericytes may be a promising approach to prevent and/or treat AD.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Circulação Cerebrovascular/fisiologia , Fragmentos de Peptídeos/metabolismo , Pericitos/fisiologia , Pericitos/transplante , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/irrigação sanguínea , Linhagem Celular Transformada , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Transgênicos , Presenilina-1/genética
13.
Int J Mol Sci ; 18(9)2017 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-28902142

RESUMO

Brain capillary endothelial cells form the blood-brain barrier (BBB), which is covered with basement membranes and is also surrounded by pericytes and astrocyte end-feet in the neurovascular unit. The BBB tightly regulates the molecular exchange between the blood flow and brain parenchyma, thereby regulating the homeostasis of the central nervous system (CNS). Thus, dysfunction of the BBB is likely involved in the pathogenesis of several neurological diseases, including Alzheimer's disease (AD). While amyloid-ß (Aß) deposition and neurofibrillary tangle formation in the brain are central pathological hallmarks in AD, cerebrovascular lesions and BBB alteration have also been shown to frequently coexist. Although further clinical studies should clarify whether BBB disruption is a specific feature of AD pathogenesis, increasing evidence indicates that each component of the neurovascular unit is significantly affected in the presence of AD-related pathologies in animal models and human patients. Conversely, since some portions of Aß are eliminated along the neurovascular unit and across the BBB, disturbing the pathways may result in exacerbated Aß accumulation in the brain. Thus, current evidence suggests that BBB dysfunction may causatively and consequently contribute to AD pathogenesis, forming a vicious cycle between brain Aß accumulation and neurovascular unit impairments during disease progression.


Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/metabolismo , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Albuminas/líquido cefalorraquidiano , Peptídeos beta-Amiloides/metabolismo , Animais , Astrócitos/metabolismo , Membrana Basal/patologia , Transporte Biológico , Sistema Nervoso Central , Angiopatia Amiloide Cerebral/metabolismo , Transtornos Cerebrovasculares/fisiopatologia , Progressão da Doença , Células Endoteliais , Homeostase , Humanos , Fragmentos de Peptídeos/metabolismo , Pericitos/metabolismo , Albumina Sérica , Junções Íntimas
14.
Neonatology ; 112(2): 180-186, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28601871

RESUMO

BACKGROUND: Hepcidin, an iron-regulatory hormone, plays a key role in preventing iron overload. Few studies have investigated the regulation of hepcidin in low-birth-weight (LBW) infants who are vulnerable to iron imbalance. OBJECTIVES: To identify perinatal factors associated with serum hepcidin levels in LBW infants. METHODS: Ninety-two LBW infants with a median gestational age (GA) of 32.6 weeks and birth weight of 1,587 g were prospectively enrolled. Serum hepcidin-25 (Hep25) levels were measured from umbilical cord blood using liquid chromatography-tandem mass spectrometry. The relationship between Hep25 levels and prematurity or other possible hepcidin-regulatory factors was evaluated. RESULTS: The median Hep25 level was 7.3 ng/mL (interquartile range: 2.85-16.38). log(Hep25) correlated with birth weight (r = 0.229, p = 0.028), log(interleukin-6 [IL-6]) (r = 0.408, p < 0.001), log(erythropoietin) (r = -0.302, p = 0.004), transferrin saturation (r = 0.29, p = 0.005), soluble transferrin receptor (r = -0.500, p < 0.001), and log(ferritin) (r = 0.696, p < 0.001). Serum iron and hemoglobin levels did not correlate with log(Hep25). Hep25 levels were higher among infants with chorioamnionitis and infants born vaginally and lower among infants born to mothers with pregnancy-induced hypertension than among infants without the respective characteristics. Stepwise multiple linear regression analysis confirmed the significant association of log(Hep25) with GA, log(IL-6), log(erythropoietin), and soluble transferrin receptor. CONCLUSIONS: Among LBW infants, GA, IL-6, erythropoietin, and soluble transferrin receptor were associated with Hep25 levels. Therefore, prematurity, inflammation, hypoxia, and erythropoietic activity may be important perinatal factors that affect hepcidin levels.


Assuntos
Sangue Fetal/química , Hepcidinas/sangue , Recém-Nascido de Baixo Peso/sangue , Adulto , Biomarcadores/sangue , Peso ao Nascer , Cromatografia Líquida , Eritropoetina/sangue , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Interleucina-6/sangue , Masculino , Estudos Prospectivos , Receptores da Transferrina/sangue , Espectrometria de Massas em Tandem
15.
CNS Drugs ; 30(9): 773-89, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27328687

RESUMO

Alzheimer's disease (AD) is a devastating neurodegenerative disorder that causes progressive cognitive decline. The majority of AD cases are sporadic and late-onset (>65 years old) making it the leading cause of dementia in the elderly. While both genetic and environmental factors contribute to the development of late-onset AD (LOAD), APOE polymorphism is a major genetic risk determinant for LOAD. In humans, the APOE gene has three major allelic variants: ε2, ε3, and ε4, of which APOE ε4 is the strongest genetic risk factor for LOAD, whereas APOE ε2 is protective. Mounting evidence suggests that APOE ε4 contributes to AD pathogenesis through multiple pathways including facilitated amyloid-ß deposition, increased tangle formation, synaptic dysfunction, exacerbated neuroinflammation, and cerebrovascular defects. Since APOE modulates multiple biological processes through its corresponding protein apolipoprotein E (apoE), APOE gene and apoE properties have been a promising target for therapy and drug development against AD. In this review, we summarize the current evidence regarding how the APOE ε4 allele contributes to the pathogenesis of AD and how relevant therapeutic approaches can be developed to target apoE-mediated pathways in AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Apolipoproteínas E/genética , Predisposição Genética para Doença , Idade de Início , Idoso , Alelos , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Animais , Desenho de Fármacos , Humanos , Terapia de Alvo Molecular , Polimorfismo Genético
16.
Acta Neuropathol ; 132(2): 225-234, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27179972

RESUMO

Cerebral amyloid angiopathy (CAA) often coexists with Alzheimer's disease (AD). APOE4 is a strong genetic risk factor for both AD and CAA. Sex-dependent differences have been shown in AD as well as in cerebrovascular diseases. Therefore, we examined the effects of APOE4, sex, and pathological components on CAA in AD subjects. A total of 428 autopsied brain samples from pathologically confirmed AD cases were analyzed. CAA severity was histologically scored in inferior parietal, middle frontal, motor, superior temporal and visual cortexes. In addition, subgroups with severe CAA (n = 60) or without CAA (n = 39) were subjected to biochemical analysis of amyloid-ß (Aß) and apolipoprotein E (apoE) by ELISA in the temporal cortex. After adjusting for age, Braak neurofibrillary tangle stage and Thal amyloid phase, we found that overall CAA scores were higher in males than females. Furthermore, carrying one or more APOE4 alleles was associated with higher overall CAA scores. Biochemical analysis revealed that the levels of detergent-soluble and detergent-insoluble Aß40, and insoluble apoE were significantly elevated in individuals with severe CAA or APOE4. The ratio of Aß40/Aß42 in insoluble fractions was also increased in the presence of CAA or APOE4, although it was negatively associated with male sex. Levels of insoluble Aß40 were positively associated with those of insoluble apoE, which were strongly influenced by CAA status. Pertaining to insoluble Aß42, the levels of apoE correlated regardless of CAA status. Our results indicate that sex and APOE genotypes differentially influence the presence and severity of CAA in AD, likely by affecting interaction and aggregation of Aß40 and apoE.


Assuntos
Doença de Alzheimer/genética , Apolipoproteína E4/genética , Encéfalo/patologia , Angiopatia Amiloide Cerebral/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Angiopatia Amiloide Cerebral/patologia , Feminino , Genótipo , Humanos , Masculino , Emaranhados Neurofibrilares/patologia , Placa Amiloide/patologia , Caracteres Sexuais
17.
J Neurosci ; 36(13): 3848-59, 2016 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-27030769

RESUMO

UNLABELLED: In Alzheimer's disease (AD), the accumulation and deposition of amyloid-ß (Aß) peptides in the brain is a central event. Aß is cleaved from amyloid precursor protein (APP) by ß-secretase and γ-secretase mainly in neurons. Although mutations inAPP,PS1, orPS2cause early-onset familial AD,ABCA7encoding ATP-binding cassette transporter A7 is one of the susceptibility genes for late-onset AD (LOAD), in which itsloss-of-functionvariants increase the disease risk. ABCA7 is homologous to a major lipid transporter ABCA1 and is highly expressed in neurons and microglia in the brain. Here, we show that ABCA7 deficiency altered brain lipid profile and impaired memory in ABCA7 knock-out (Abca7(-/-)) mice. When bred to amyloid model APP/PS1 mice, plaque burden was exacerbated by ABCA7 deficit.In vivomicrodialysis studies indicated that the clearance rate of Aß was unaltered. Interestingly, ABCA7 deletion facilitated the processing of APP to Aß by increasing the levels of ß-site APP cleaving enzyme 1 (BACE1) and sterol regulatory element-binding protein 2 (SREBP2) in primary neurons and mouse brains. Knock-down of ABCA7 expression in neurons caused endoplasmic reticulum stress highlighted by increased level of protein kinase R-like endoplasmic reticulum kinase (PERK) and increased phosphorylation of eukaryotic initiation factor 2α (eIF2α). In the brains of APP/PS1;Abca7(-/-)mice, the level of phosphorylated extracellular regulated kinase (ERK) was also significantly elevated. Together, our results reveal novel pathways underlying the association of ABCA7 dysfunction and LOAD pathogenesis. SIGNIFICANCE STATEMENT: Gene variants inABCA7encoding ATP-binding cassette transporter A7 are associated with the increased risk for late-onset Alzheimer's disease (AD). Importantly, we found the altered brain lipid profile and impaired memory in ABCA7 knock-out mice. The accumulation of amyloid-ß (Aß) peptides cleaved from amyloid precursor protein (APP) in the brain is a key event in AD pathogenesis and we also found that ABCA7 deficit exacerbated brain Aß deposition in amyloid AD model APP/PS1 mice. Mechanistically, we found that ABCA7 deletion facilitated the processing of APP and Aß production by increasing the levels of ß-secretase 1 (BACE1) in primary neurons and mouse brains without affecting the Aß clearance rate in APP/PS1 mice. Our study demonstrates a novel mechanism underlying how dysfunctions of ABCA7 contribute to the risk for AD.


Assuntos
Transportadores de Cassetes de Ligação de ATP/deficiência , Doença de Alzheimer , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Regulação da Expressão Gênica/genética , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Fator de Iniciação 2 em Eucariotos/metabolismo , Feminino , Humanos , Metabolismo dos Lipídeos/genética , Masculino , Transtornos da Memória/genética , Camundongos , Camundongos Transgênicos , Mutação/genética , Presenilina-1/genética , Transdução de Sinais/genética
18.
Stroke ; 47(4): 1068-77, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26883501

RESUMO

BACKGROUND AND PURPOSE: Age-related changes in the cerebrovasculature, including blood-brain barrier (BBB) disruption, are emerging as potential risks for diverse neurological conditions. Because the accumulation of senescent cells in tissues is increasingly recognized as a critical step leading to age-related organ dysfunction, we evaluated whether senescent vascular cells are associated with compromised BBB integrity. METHODS: Effects of vascular cell senescence on tight junction and barrier integrity were studied using an in vitro BBB model, composed of endothelial cells, pericytes, and astrocytes. In addition, tight junction coverage in microvessels and BBB integrity in BubR1 hypomorphic (BubR1(H/H)) mice, which display senescence cell-dependent phenotypes, were examined. RESULTS: When an in vitro BBB model was constructed with senescent endothelial cells and pericytes, tight junction structure and barrier integrity (evaluated by transendothelial electric resistance and tracer efflux assay using sodium fluorescein and Evans blue-albumin were significantly impaired. Endothelial cells and pericytes from BubR1(H/H) mice had increased senescent-associated ß-galactosidase activity and p16(INK4a) expression, demonstrating an exacerbation of senescence. The coverage by tight junction proteins in the cortical microvessels were reduced in BubR1(H/H) mice, consistent with a compromised BBB integrity from permeability assays. Importantly, the coverage of microvessels by end-feet of aquaporin 4-immunoreactive astrocytes was not altered in the cortex of the BubR1(H/H) mice. CONCLUSIONS: Our results indicate that accumulation of senescent vascular cells is associated with compromised BBB integrity, providing insights into the mechanism of BBB disruption related to biological aging.


Assuntos
Envelhecimento/patologia , Barreira Hematoencefálica/patologia , Senescência Celular/fisiologia , Células Endoteliais/patologia , Pericitos/patologia , Envelhecimento/metabolismo , Animais , Aquaporina 4/metabolismo , Astrócitos/metabolismo , Astrócitos/patologia , Barreira Hematoencefálica/metabolismo , Encéfalo/irrigação sanguínea , Permeabilidade Capilar , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Células Endoteliais/metabolismo , Camundongos , Pericitos/metabolismo , Junções Íntimas/metabolismo , beta-Galactosidase/metabolismo
19.
Chem Sci ; 7(9): 5770-5774, 2016 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30034715

RESUMO

Lithium-encapsulated [60]fullerene Li@C60, namely, lithium-ion-encapsulated [60]fullerene radical anion Li+@C60˙-, was synthesised by electrochemical reduction of lithium-ion-encapsulated [60]fullerene trifluoromethanesulfonylimide salt [Li+@C60](TFSI-). The product was fully characterised by UV-vis-NIR absorption and ESR spectroscopy as well as single-crystal X-ray analysis for the co-crystal with nickel octaethylporphyrin. In solution Li@C60 exists as a monomer form dominantly, while in the crystal state it forms a dimer (Li@C60-Li@C60) through coupling of the C60 radical anion cage. These structural features were supported by DFT calculations at the M06-2X/6-31G(d) level of theory.

20.
Exp Neurol ; 277: 1-9, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26688581

RESUMO

Apolipoprotein E (apoE) plays a critical role in maintaining synaptic integrity by transporting cholesterol to neurons through the low-density lipoprotein receptor related protein-1 (LRP1). Bexarotene, a retinoid X receptor (RXR) agonist, has been reported to have potential beneficial effects on cognition by increasing brain apoE levels and lipidation. To investigate the effects of bexarotene on aging-related synapse loss and the contribution of neuronal LRP1 to the pathway, forebrain neuron-specific LRP1 knockout (nLrp1(-/-)) and littermate control mice were administered with bexarotene-formulated diet (100mg/kg/day) or control diet at the age of 20-24 months for 8 weeks. Upon bexarotene treatment, levels of brain apoE and ATP-binding cassette sub-family A member 1 (ABCA1) were significantly increased in both mice. While levels of PSD95, glutamate receptor 1 (GluR1), and N-methyl-d-aspartate receptor NR1 subunit (NR1), which are key postsynaptic proteins that regulate synaptic plasticity, were decreased with aging, they were restored by bexarotene treatment in the brains of control but not nLrp1(-/-) mice. These results indicate that the beneficial effects of bexarotene on synaptic integrity depend on the presence of neuronal LRP1. However, we also found that bexarotene treatment led to the activation of glial cells, weight loss and hepatomegaly, which are likely due to hepatic failure. Taken together, our results demonstrate that apoE-targeted treatment through the RXR pathway has a potential beneficial effect on synapses during aging; however, the therapeutic application of bexarotene requires extreme caution due to its toxic side effects.


Assuntos
Envelhecimento/efeitos dos fármacos , Encéfalo/citologia , Receptores de LDL/deficiência , Receptores X Retinoide/agonistas , Sinapses/efeitos dos fármacos , Tetra-Hidronaftalenos/administração & dosagem , Proteínas Supressoras de Tumor/deficiência , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Apolipoproteínas E/metabolismo , Bexaroteno , Encéfalo/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteína 4 Homóloga a Disks-Large , Regulação da Expressão Gênica/efeitos dos fármacos , Guanilato Quinases/metabolismo , Hepatopatias/etiologia , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas dos Microfilamentos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Receptores de AMPA/metabolismo , Receptores de LDL/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/metabolismo , Proteínas Supressoras de Tumor/genética
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