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1.
Zhongguo Zhen Jiu ; 41(3): 295-302, 2021 Mar 12.
Artigo em Chinês | MEDLINE | ID: mdl-33798313

RESUMO

OBJECTIVE: To screen protein target in prevention and treatment with electroacupuncture (EA) for Alzheimer's disease (AD) and explore the potential mechanism of EA in prevention of AD. METHODS: A total of 40 APP/PS1 transgenic young male mice, 1.5-month old, were randomized into an EA group and a model group, 20 mice in each one, and 20 C57BL/6J mice were chosen as the normal control group. After adaptive housing for 1 week, the mice in the EA group were stimulated with EA at "Baihui" (GV 20), "Fengfu" (GV 16) and "Shenshu" (BL 23), with intermittent wave, 10 Hz in frequency and 2 mA in electric intensity. EA was given once daily, 20 min each time. There was 1 day at interval after EA for 6 days each week. Totally, the intervention lasted for 16 weeks. On day 3 after the end of EA intervention, Morris water maze test was adopted to detect learning and memory abilities of mice in each group. After water maze test, the label-free method was used to measure the difference expressions in cerebral cortex and hippocampus. Using Western blot method, the expressions of guanylate binding protein beta 5 (GNB 5) and histone-H 3 in cerebral cortex and hippocampus were verified. Using immunohistochemical method, the expressions of amyloid beta protein (Aß) in cerebral cortex and hippocampus were detected. RESULTS: Compared with the normal control group, the escape latency (on day 2, 3 and 4) was prolonged, the frequency of crossing platform and the duration of platform stay were decreased in the mice of the model group (P<0.05). Compared with the model group, the escape latency (on day 3 and 4) was shortened, the frequency of crossing platform and the duration of platform stay were increased in the mice of the EA group (P<0.05). By the comparison among the three groups, the high mobility group nucleosome-binding domain-containing protein 5, band 3 anion transport protein, histone-H 3, epoxide hydrolase 4 (fragment), neurolysin (mitochondria), phosphoglycerate mutase 2, GNB5 and Aß were the differential proteins with the larger fold-change difference in expression. Compared with the normal control group, the expression of histone-H 3 in cerebral cortex and hippocampus was reduced (P<0.001) and the expressions of GNB 5 and Aß were increased (P<0.001, P<0.01) in the mice of the model group. Compared with the model group, the expression of histone-H 3 in cerebral cortex and hippocampus was increased (P<0.001) and the expressions of GNB 5 and Aßwere reduced (P<0.001, P<0.05) in the mice of the EA group. CONCLUSION: The intervention with EA effectively prevents from the decline of learning and memory ability and the formation of Aß senile plaques in cerebral cortex and hippocampus in young mouse models of AD after growing up. Besides, EA plays a regulatory function for protein expression differences induced by AD model.


Assuntos
Doença de Alzheimer , Eletroacupuntura , Doença de Alzheimer/genética , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/genética , Animais , Modelos Animais de Doenças , Hipocampo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteômica
2.
Molecules ; 26(5)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652938

RESUMO

PET of ß-Amyloid plaques (Aß) using [18F]florbetaben ([18F]FBB) and [18F]fluorodeoxyglucose ([18F]FDG) increasingly aid clinicians in early diagnosis of dementia, including Alzheimer's disease (AD), frontotemporal disease, dementia with Lewy bodies, and vascular dementia. The aim of this retrospective analysis was to evaluate clinical relevance of [18F]FBB, [18F]FDG PET and complimentary CSF measurements in patients with suspected dementia. In this study, 40 patients with clinically suspected or history of dementia underwent (1) measurement of Aß peptides, total tau, and p-tau protein levels in the cerebrospinal fluid (CSF) compared with healthy controls (HC); (2) clinical and neuropsychological assessment, which included Consortium to Establish a Registry for Alzheimer's Disease neuropsychological assessment battery (CERAD-NAB); (3) [18F]FBB and [18F]FDG PET imaging within an average of 3 weeks. The subjects were within 15 days stratified using PET, CSF measurements as HC, mild cognitive impaired (MCI) and dementia including Alzheimer´s disease. The predictive dementia-related cognitive decline values were supporting the measurements. PET images were evaluated visually and quantitatively using standard uptake value ratios (SUVR). Twenty-one (52.5%) subjects were amyloid-positive (Aß+), with a median neocortical SUVR of 1.80 for AD versus 1.20 relative to the respective 19 (47.5 %) amyloid-negative (Aß-) subjects. Moreover, the [18F]FDG and [18F]FBB confirmed within a sub-group of 10 patients a good complimentary role by correlation between amyloid pathology and brain glucose metabolism in 8 out of 10 subjects. The results suggest the clinical relevance for [18F]FBB combined with [18F]FDG PET retention and CFS measurements serving the management of our patients with dementia. Therefore, [18F]FBB combined with [18F]FDG PET is a helpful tool for differential diagnosis, and supports the patients' management as well as treatment.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Demência/diagnóstico por imagem , Fluordesoxiglucose F18/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/isolamento & purificação , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/fisiopatologia , Demência/diagnóstico , Demência/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Proteínas tau/genética , Proteínas tau/isolamento & purificação
3.
Molecules ; 26(4)2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33670093

RESUMO

The misfolding and aggregation of polypeptide chains into ß-sheet-rich amyloid fibrils is associated with a wide range of neurodegenerative diseases. Growing evidence indicates that the oligomeric intermediates populated in the early stages of amyloid formation rather than the mature fibrils are responsible for the cytotoxicity and pathology and are potentially therapeutic targets. However, due to the low-populated, transient, and heterogeneous nature of amyloid oligomers, they are hard to characterize by conventional bulk methods. The development of single molecule approaches provides a powerful toolkit for investigating these oligomeric intermediates as well as the complex process of amyloid aggregation at molecular resolution. In this review, we present an overview of recent progress in characterizing the oligomerization of amyloid proteins by single molecule fluorescence techniques, including single-molecule Förster resonance energy transfer (smFRET), fluorescence correlation spectroscopy (FCS), single-molecule photobleaching and super-resolution optical imaging. We discuss how these techniques have been applied to investigate the different aspects of amyloid oligomers and facilitate understanding of the mechanism of amyloid aggregation.


Assuntos
Peptídeos beta-Amiloides/química , Amiloide/química , Proteínas Amiloidogênicas/química , Agregação Patológica de Proteínas/genética , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/ultraestrutura , Proteínas Amiloidogênicas/genética , Proteínas Amiloidogênicas/ultraestrutura , Transferência Ressonante de Energia de Fluorescência , Humanos , Cinética , Conformação Proteica em Folha beta/genética , Imagem Individual de Molécula , Espectrometria de Fluorescência
4.
Am J Hum Genet ; 107(4): 714-726, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32961112

RESUMO

Transcriptome-wide association studies (TWASs) have been widely used to integrate gene expression and genetic data for studying complex traits. Due to the computational burden, existing TWAS methods do not assess distant trans-expression quantitative trait loci (eQTL) that are known to explain important expression variation for most genes. We propose a Bayesian genome-wide TWAS (BGW-TWAS) method that leverages both cis- and trans-eQTL information for a TWAS. Our BGW-TWAS method is based on Bayesian variable selection regression, which not only accounts for cis- and trans-eQTL of the target gene but also enables efficient computation by using summary statistics from standard eQTL analyses. Our simulation studies illustrated that BGW-TWASs achieved higher power compared to existing TWAS methods that do not assess trans-eQTL information. We further applied BWG-TWAS to individual-level GWAS data (N = ∼3.3K), which identified significant associations between the genetically regulated gene expression (GReX) of ZC3H12B and Alzheimer dementia (AD) (p value = 5.42 × 10-13), neurofibrillary tangle density (p value = 1.89 × 10-6), and global measure of AD pathology (p value = 9.59 × 10-7). These associations for ZC3H12B were completely driven by trans-eQTL. Additionally, the GReX of KCTD12 was found to be significantly associated with ß-amyloid (p value = 3.44 × 10-8) which was driven by both cis- and trans-eQTL. Four of the top driven trans-eQTL of ZC3H12B are located within APOC1, a known major risk gene of AD and blood lipids. Additionally, by applying BGW-TWAS with summary-level GWAS data of AD (N = ∼54K), we identified 13 significant genes including known GWAS risk genes HLA-DRB1 and APOC1, as well as ZC3H12B.


Assuntos
Doença de Alzheimer/genética , Apolipoproteína C-I/genética , Genoma Humano , Modelos Estatísticos , Proteínas/genética , Locos de Características Quantitativas , Ribonucleases/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Apolipoproteína C-I/metabolismo , Teorema de Bayes , Estudos de Casos e Controles , Simulação por Computador , Feminino , Expressão Gênica , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB1/metabolismo , Humanos , Masculino , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Proteínas/metabolismo , Ribonucleases/metabolismo , Transcriptoma
5.
Nat Genet ; 52(10): 1024-1035, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32989324

RESUMO

Protein aggregation is the hallmark of neurodegeneration, but the molecular mechanisms underlying late-onset Alzheimer's disease (AD) are unclear. Here we integrated transcriptomic, proteomic and epigenomic analyses of postmortem human brains to identify molecular pathways involved in AD. RNA sequencing analysis revealed upregulation of transcription- and chromatin-related genes, including the histone acetyltransferases for H3K27ac and H3K9ac. An unbiased proteomic screening singled out H3K27ac and H3K9ac as the main enrichments specific to AD. In turn, epigenomic profiling revealed gains in the histone H3 modifications H3K27ac and H3K9ac linked to transcription, chromatin and disease pathways in AD. Increasing genome-wide H3K27ac and H3K9ac in a fly model of AD exacerbated amyloid-ß42-driven neurodegeneration. Together, these findings suggest that AD involves a reconfiguration of the epigenome, wherein H3K27ac and H3K9ac affect disease pathways by dysregulating transcription- and chromatin-gene feedback loops. The identification of this process highlights potential epigenetic strategies for early-stage disease treatment.


Assuntos
Doença de Alzheimer/genética , Agregação Patológica de Proteínas/genética , Proteoma/genética , Transcriptoma/genética , Acetilação , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Cromatina/genética , Epigenoma/genética , Histona Acetiltransferases/genética , Código das Histonas/genética , Histonas/genética , Humanos , Fragmentos de Peptídeos/genética , Agregação Patológica de Proteínas/patologia , Transdução de Sinais/genética , Ativação Transcricional/genética
6.
Neurology ; 95(17): e2354-e2365, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-32928967

RESUMO

OBJECTIVE: To investigate the association between APOE genotype and ß-amyloid (Aß) burden, as measured by PET in patients with subcortical vascular cognitive impairment (SVCI) and those with Alzheimer disease-related cognitive impairment (ADCI). METHODS: This was a cross-sectional study of 310 patients with SVCI and 999 with ADCI. To evaluate the effects of APOE genotype or diagnostic group on Aß positivity, we performed multivariate logistic regression analyses. Further distinctive underlying features of latent subgroups were examined by employing a latent class cluster analysis approach. RESULTS: In comparison with ε3 homozygotes, in the ADCI group, ε2 carriers showed a lower frequency of Aß positivity (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.23-0.79), while in the SVCI group, ε2 carriers showed a higher frequency of Aß positivity (OR 2.26, 95% CI 1.02-5.01). In particular, we observed an interaction effect of ε2 carrier status and diagnostic group on Aß positivity (OR 5.12, 95% CI 1.93-13.56), in that relative to ε3 homozygotes, there were more Aß-positive ε2 carriers in the SVCI group than in the ADCI group. We also identified latent subgroups of Aß-positive APOE ε2 carriers with SVCI and Aß-positive APOE ε4 carriers with ADCI. CONCLUSIONS: Our findings suggest that APOE ε2 is distinctly associated with Aß deposition in patients with SVCI and those with ADCI. Our findings further suggest that there is a distinctive subgroup of Aß-positive APOE ε2 carriers with SVCI among patients with cognitive impairment.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Apolipoproteína E2/genética , Demência Vascular/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/epidemiologia , Carga Corporal (Radioterapia) , Disfunção Cognitiva/genética , Estudos Transversais , Demência Vascular/diagnóstico por imagem , Demência Vascular/epidemiologia , Feminino , Predisposição Genética para Doença , Genótipo , Heterozigoto , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Prevalência
7.
PLoS One ; 15(9): e0239584, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32966331

RESUMO

Familial forms of Alzheimer's disease (AD) are caused by mutations in the presenilin genes or in the gene encoding for the amyloid precursor protein (APP). Proteolytic cleavage of APP generates the ß-amyloid peptide (Aß), which aggregates into amyloid plaques, one of the major hallmarks of AD. APP mutations within the Aß sequence, so-called intra-Aß mutations, cluster around position E693 of APP, which corresponds to position E22 in the Aß sequence. One of these mutations is the Osaka mutation, E693Δ, which has unique aggregation properties with patients showing unusually low brain amyloid levels on amyloid PET scans. Despite intense research on the pathomechanisms of different intra-Aß mutants, our knowledge is limited due to controversial findings in various studies. Here, we investigated in an ex vivo experimental system the neuro- and synaptotoxic properties of two intra-Aß mutants with different intrinsic aggregation propensities, the Osaka mutation E22Δ and the Arctic mutation E22G, and compared them to wild-type (wt) Aß. Experiments in hippocampal slice cultures from transgenic mice were complemented by treating wild-type slices with recombinantly produced Aß40 or Aß42 containing the respective intra-Aß mutations. Our analyses revealed that wt Aß and E22G Aß, both recombinant and transgenic, caused a loss of dendritic spines along with an increase in tau phosphorylation and tau-dependent neurodegeneration. In all experiments, the 42-residue variants of wt and E22G Aß showed stronger effects than the respective Aß40 isoforms. In contrast, E22Δ Aß neither reduced dendritic spine density nor resulted in increased tau phosphorylation or neuronal cell death in our ex vivo system. Our findings suggest that the previously reported major differences in the aggregation kinetics between E22G and E22Δ Aß are likely reflected in different disease pathomechanisms.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/genética , Proteínas Mutantes/genética , Mutação , Proteínas tau/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Animais , Morte Celular , Espinhas Dendríticas/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Técnicas In Vitro , Cinética , Camundongos , Camundongos Transgênicos , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Fosforilação , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Sinapses/patologia
8.
Neurology ; 95(11): e1554-e1564, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32759192

RESUMO

OBJECTIVE: To determine whether years of education and the ε4 risk allele at APOE influence ß-amyloid (Aß) pathology similarly in asymptomatic individuals with a family history of sporadic Alzheimer disease (AD) and presymptomatic autosomal dominant AD mutation carriers. METHODS: We analyzed cross-sectional data from 106 asymptomatic individuals with a parental history of sporadic AD (PREVENT-AD cohort; age 67.28 ± 4.72 years) and 117 presymptomatic autosomal dominant AD mutation carriers (DIAN cohort; age 35.04 ± 9.43 years). All participants underwent structural MRI and Aß-PET imaging. In each cohort we investigated the influence of years of education, APOE ε4 status, and their interaction on Aß-PET. RESULTS: Asymptomatic individuals with a parental history of sporadic AD showed increased Aß burden associated with APOE ε4 carriage and lower level of education, but no interaction between these. Presymptomatic mutation carriers of autosomal dominant AD showed no relation between APOE ε4 and Aß burden, but increasing level of education was associated with reduced Aß burden. The association between educational attainment and Aß burden was similar in the 2 cohorts. CONCLUSIONS: While the APOE ε4 allele confers increased tendency toward Aß accumulation in sporadic AD only, protective environmental factors, like increased education, may promote brain resistance against Aß pathology in both sporadic and autosomal dominant AD.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Apolipoproteína E4/genética , Escolaridade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
Proc Natl Acad Sci U S A ; 117(33): 19926-19937, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32732434

RESUMO

The early events in the aggregation of the intrinsically disordered peptide, amyloid-ß (Aß), involve transitions from the disordered free energy ground state to assembly-competent states. Are the fingerprints of order found in the amyloid fibrils encoded in the conformations that the monomers access at equilibrium? If so, could the enhanced aggregation rate of Aß42 compared to Aß40 be rationalized from the sparsely populated high free energy states of the monomers? Here, we answer these questions in the affirmative using coarse-grained simulations of the self-organized polymer-intrinsically disordered protein (SOP-IDP) model of Aß40 and Aß42. Although both the peptides have practically identical ensemble-averaged properties, characteristic of random coils (RCs), the conformational ensembles of the two monomers exhibit sequence-specific heterogeneity. Hierarchical clustering of conformations reveals that both the peptides populate high free energy aggregation-prone ([Formula: see text]) states, which resemble the monomers in the fibril structure. The free energy gap between the ground (RC) and the [Formula: see text] states of Aß42 peptide is smaller than that for Aß40. By relating the populations of excited states of the two peptides to the fibril formation time scales using an empirical formula, we explain nearly quantitatively the faster aggregation rate of Aß42 relative to Aß40. The [Formula: see text] concept accounts for fibril polymorphs, leading to the prediction that the less stable [Formula: see text] state of Aß42, encoding for the U-bend fibril, should form earlier than the structure with the S-bend topology, which is in accord with Ostwald's rule rationalizing crystal polymorph formation.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/química , Fragmentos de Peptídeos/química , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Entropia , Humanos , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos
10.
PLoS One ; 15(7): e0236318, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726319

RESUMO

Lately, Drosophila has been favored as a model in sleep and circadian rhythm research due to its conserved mechanism and easily manageable operation. These studies have revealed the sophisticated parameters in whole-day sleep profiles of Drosophila, drawing connections between Drosophila sleep and human sleep. In this study, we tested several sleep deprivation protocols (mechanical shakes and light interruptions) on Drosophila and delineated their influences on Drosophila sleep. We applied a daytime light-deprivation protocol (DD) mimicking jet-lag to screen drugs that alleviate sleep deprivation. Characteristically, classical sleep-aid compounds exhibited different forms of influence: phenobarbital and pentobarbital modified total sleep time, while melatonin only shortened the latency to sleep. Such results construct the basis for further research on sleep benefits in other treatments in Drosophila. We screened seven herb extracts, and found very diverse results regarding their effect on sleep regulation. For instance, Panax notoginseng and Withania somnifera extracts displayed potent influence on total sleep time, while Melissa officinalis increased the number of sleep episodes. By comparing these treatments, we were able to rank drug potency in different aspects of sleep regulation. Notably, we also confirmed the presence of sleep difficulties in a Drosophila Alzheimer's disease (AD) model with an overexpression of human Abeta, and recognized clear differences between the portfolios of drug screening effects in AD flies and in the control group. Overall, potential drug candidates and receipts for sleep problems can be identified separately for normal and AD Drosophila populations, outlining Drosophila's potential in drug screening tests in other populations if combined with the use of other genetic disease tools.


Assuntos
Extratos Vegetais/farmacologia , Privação do Sono/tratamento farmacológico , Transtornos do Sono-Vigília/tratamento farmacológico , Sono/fisiologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/genética , Animais , Ritmo Circadiano/efeitos dos fármacos , Modelos Animais de Doenças , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Regulação da Expressão Gênica/genética , Humanos , Melatonina/farmacologia , Mutação , Panax notoginseng/química , Fenobarbital/farmacologia , Extratos Vegetais/química , Sono/efeitos dos fármacos , Sono/genética , Privação do Sono/genética , Privação do Sono/fisiopatologia , Transtornos do Sono-Vigília/genética , Transtornos do Sono-Vigília/fisiopatologia , Withania/química
11.
PLoS One ; 15(7): e0235543, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645028

RESUMO

Senile plaques frequently contain Aß-pE(3), a N-terminally truncated Aß species that is more closely linked to AD compared to other Aß species. Tau protein is highly phosphorylated at several residues in AD, and specifically phosphorylation at Ser202/Thr205 is known to be increased in AD. Several studies suggest that formation of plaques and tau phosphorylation might be linked to each other. To evaluate if Aß-pE(3) and ptau Ser202/Thr205 levels correlate in human and transgenic AD mouse models, we analyzed human cortical and hippocampal brain tissue of different Braak stages as well as murine brain tissue of two transgenic mouse models for levels of Aß-pE(3) and ptau Ser202/Thr205 and correlated the data. Our results show that Aß-pE(3) formation is increased at early Braak stages while ptau Ser202/Thr205 mostly increases at later stages. Further analyses revealed strongest correlations between the two pathologies in the temporal, frontal, cingulate, and occipital cortex, however correlation in the hippocampus was weaker. Evaluation of murine transgenic brain tissue demonstrated a slow but steady increase of Aß-pE(3) from 6 to 12 months of age in the cortex and hippocampus of APPSL mice, and a very early and strong Aß-pE(3) increase in 5xFAD mice. ptau Ser202/Thr205 levels increased at the age of 9 months in APPSL mice and at 6 months in 5xFAD mice. Our results show that Aß-pE(3) and ptau Ser202/Thr205 levels strongly correlate in human as well as murine tissues, suggesting that tau phosphorylation might be amplified by Aß-pE(3).


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/genética , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Fosforilação , Ácido Pirrolidonocarboxílico/química , Especificidade da Espécie , Proteínas tau/genética
12.
Arch Biochem Biophys ; 690: 108446, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32593678

RESUMO

A simple NMR method to analyze the data obtained by NMR titration experiment of amyloid formation inhibitors against uniformly 15N-labeled amyloid-ß 1-42 peptide (Aß(1-42)) was described. By using solution nuclear magnetic resonance (NMR) measurement, the simplest method for monitoring the effects of Aß fibrilization inhibitors is the NMR chemical shift perturbation (CSP) experiment using 15N-labeled Aß(1-42). However, the flexible and dynamic nature of Aß(1-42) monomer may hamper the interpretation of CSP data. Here we introduced principal component analysis (PCA) for visualizing and analyzing NMR data of Aß(1-42) in the presence of amyloid inhibitors including high concentration osmolytes. We measured 1H-15N 2D spectra of Aß(1-42) at various temperatures as well as of Aß(1-42) with several inhibitors, and subjected all the data to PCA (PCA-HSQC). The PCA diagram succeeded in differentiating the various amyloid inhibitors, including epigallocatechin gallate (EGCg), rosmarinic acid (RA) and curcumin (CUR) from high concentration osmolytes. We hypothesized that the CSPs reflected the conformational equilibrium of intrinsically disordered Aß(1-42) induced by weak inhibitor binding rather than the specific molecular interactions.


Assuntos
Peptídeos beta-Amiloides/química , Fenóis/química , Análise de Componente Principal/métodos , Amiloide/metabolismo , Peptídeos beta-Amiloides/genética , Catequina/análogos & derivados , Catequina/química , Cinamatos/química , Curcumina/química , Depsídeos/química , Escherichia coli/genética , Humanos , Espectroscopia de Ressonância Magnética , Isótopos de Nitrogênio/química , Conformação Proteica , Temperatura , Termodinâmica
13.
Proc Natl Acad Sci U S A ; 117(25): 14482-14492, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32518112

RESUMO

Cerebral amyloid angiopathy (CAA), where beta-amyloid (Aß) deposits around cerebral blood vessels, is a major contributor of vascular dysfunction in Alzheimer's disease (AD) patients. However, the molecular mechanism underlying CAA formation and CAA-induced cerebrovascular pathology is unclear. Hereditary cerebral amyloid angiopathy (HCAA) is a rare familial form of CAA in which mutations within the (Aß) peptide cause an increase in vascular deposits. Since the interaction between Aß and fibrinogen increases CAA and plays an important role in cerebrovascular damage in AD, we investigated the role of the Aß-fibrinogen interaction in HCAA pathology. Our work revealed the most common forms of HCAA-linked mutations, Dutch (E22Q) and Iowa (D23N), resulted in up to a 50-fold stronger binding affinity of Aß for fibrinogen. In addition, the stronger interaction between fibrinogen and mutant Aßs led to a dramatic perturbation of clot structure and delayed fibrinolysis. Immunofluorescence analysis of the occipital cortex showed an increase of fibrin(ogen)/Aß codeposition, as well as fibrin deposits in HCAA patients, compared to early-onset AD patients and nondemented individuals. Our results suggest the HCAA-type Dutch and Iowa mutations increase the interaction between fibrinogen and Aß, which might be central to cerebrovascular pathologies observed in HCAA.


Assuntos
Peptídeos beta-Amiloides/genética , Encéfalo/patologia , Angiopatia Amiloide Cerebral Familiar/patologia , Fibrina/metabolismo , Fibrinogênio/metabolismo , Fragmentos de Peptídeos/genética , Peptídeos beta-Amiloides/metabolismo , Angiopatia Amiloide Cerebral Familiar/genética , Feminino , Fibrinogênio/isolamento & purificação , Fibrinólise/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fragmentos de Peptídeos/metabolismo , Ligação Proteica/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo
14.
Am J Chin Med ; 48(4): 945-966, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32476431

RESUMO

Tetramethylpyrazine has shown neuroprotective and axonal outgrowth-promoting effects and can improve cognitive deficit in a rat model of chronic hypoperfusion. However, the role of tetramethylpyrazine in sevoflurane-induced neurotoxicity is still vague. Therefore, this study was designed to investigate the effects and mechanisms of tetramethylpyrazine on sevoflurane-induced autophagy, apoptosis, and the expression of BACE1 and A[Formula: see text] in SH-SY5Y cells. We measured the expression levels of the apoptosis protein markers Bax and Bcl-2, autophagy protein markers Atg5 and LC3-II, BACE1, and A[Formula: see text] in SH-SY5Y cells after sevoflurane treatment and determined the effects of tetramethylpyrazine on sevoflurane-induced expression of these proteins after silencing GPR50 or Atg5 with siRNA in vitro. We found that exposure to 3.4% sevoflurane for 6 h decreased the expression of autophagy protein markers and increased the expression of the apoptosis protein markers, BACE1, and A[Formula: see text] in SH-SY5Y cells. The number of red puncta (autolysosomes) and yellow puncta (autophagosomes) in each SH-SY5Y cell decreased after transient transfection with the mRFP-GFP-LC3 expression plasmid. Silencing of GPR50 decreased the expression of pCREB, Atg5, and LC3-II, while silencing of Atg5 increased the expression of BACE1 and A[Formula: see text] in SH-SY5Y cells. Our results demonstrate that tetramethylpyrazine attenuated sevoflurane-induced neurotoxicity by enhancing autophagy through the GPR50/CREB pathway in SH-SY5Y cells.


Assuntos
Autofagia/efeitos dos fármacos , Autofagia/genética , Proteína de Ligação a CREB/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neuroprostanos , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Receptores Acoplados a Proteínas-G/metabolismo , Sevoflurano/toxicidade , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Células Tumorais Cultivadas
15.
Biochem Pharmacol ; 177: 113997, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32353422

RESUMO

Alzheimer's disease (AD) is an irreversible neurodegenerative brain disorder with complex pathogenesis. The fibrillar peptide ß-amyloid (Aß) has a chief function in the pathogenesis of AD. Emerging evidence has indicated that there is a tight relationship between inflammation, mitochondrial dysfunction and Aß formation. 2,3,5,4'-Tetrahydroxystilbene-2-O-ß-D-glucoside (TSG) is one of the main active components extracted from Polygonum multiflorum. Recent research corroborated the beneficial roles of TSG in alleviating the learning and memory of AD models. Unfortunately, the underlying mechanism of TSG remains poorly elucidated. The purpose of the present study was to investigate the effects of TSG on LPS/ATP and Aß25-35-induced inflammation in microglia and neurons and its underlying molecular mechanisms. Our results found that treatment with TSG significantly attenuated the secretion of inflammatory cytokines, reduced NLRP3 inflammasome, and regulated mitophagy. TSG efficiently alleviated LPS-induced inflammatory response by inhibiting the NLRP3 signaling pathway both in microglia and neuron. Meanwhile, TSG promoted autophagy involved in the AMPK/PINK1/Parkin signaling pathway, which may contribute to the protective activity. Additional mechanistic investigations to evaluate the dependence of the neuroprotective role of TSG on PINK1 revealed that a lack of PINK1 inhibited autophagy, especially mitophagy in microglia. Importantly, knockdown of PINK1 or Parkin by siRNA or CRISPR/Cas9 system abolished the protective effects of TSG. In conclusion, these phenomena suggested that TSG prevented LPS/ATP and Aß-induced inflammation via AMPK/PINK1/Parkin-dependent enhancement of mitophagy. We found the neuroprotective effect of TSG, suggesting it may be beneficial for AD prevention and treatment by suppressing the activation of inflammation.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Glucosídeos/farmacologia , Fármacos Neuroprotetores/farmacologia , Proteínas Quinases/genética , Estilbenos/farmacologia , Ubiquitina-Proteína Ligases/genética , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Linhagem Celular Tumoral , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/genética , Inflamassomos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/citologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitofagia/efeitos dos fármacos , Mitofagia/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Cultura Primária de Células , Proteínas Quinases/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/metabolismo
16.
PLoS One ; 15(5): e0232785, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32469871

RESUMO

BACKGROUND: Alzheimer's disease (AD) pathology precedes symptoms and its detection can identify at-risk individuals who may benefit from early treatment. Since the retinal nerve fiber layer (RNFL) is depleted in established AD, we tested whether its thickness can predict whether cognitively healthy (CH) individuals have a normal or pathological cerebrospinal fluid (CSF) Aß42 (A) and tau (T) ratio. METHODS: As part of an ongoing longitudinal study, we enrolled CH individuals, excluding those with cognitive impairment and significant ocular pathology. We classified the CH group into two sub-groups, normal (CH-NAT, n = 16) or pathological (CH-PAT, n = 27), using a logistic regression model from the CSF AT ratio that identified >85% of patients with a clinically probable AD diagnosis. Spectral-domain optical coherence tomography (OCT) was acquired for RNFL, ganglion cell-inner plexiform layer (GC-IPL), and macular thickness. Group differences were tested using mixed model repeated measures and a classification model derived using multiple logistic regression. RESULTS: Mean age (± standard deviation) in the CH-PAT group (n = 27; 75.2 ± 8.4 years) was similar (p = 0.50) to the CH-NAT group (n = 16; 74.1 ± 7.9 years). Mean RNFL (standard error) was thinner in the CH-PAT group by 9.8 (2.7) µm; p < 0.001. RNFL thickness classified CH-NAT vs. CH-PAT with 87% sensitivity and 56.3% specificity. CONCLUSIONS: Our retinal data predict which individuals have CSF biomarkers of AD pathology before cognitive deficits are detectable with 87% sensitivity. Such results from easy-to-acquire, objective and non-invasive measurements of the RNFL merit further study of OCT technology to monitor or screen for early AD pathology.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Disfunção Cognitiva/genética , Proteínas tau/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Amiloidose/líquido cefalorraquidiano , Amiloidose/diagnóstico por imagem , Amiloidose/genética , Amiloidose/patologia , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fibras Nervosas/metabolismo , Fibras Nervosas/patologia , Disco Óptico/diagnóstico por imagem , Disco Óptico/metabolismo , Disco Óptico/patologia , Retina/diagnóstico por imagem , Retina/metabolismo , Retina/patologia , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Tomografia de Coerência Óptica , Proteínas tau/líquido cefalorraquidiano
17.
PLoS One ; 15(5): e0233700, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32469963

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and amyloid-beta (Aß) depositions generated by the proteolysis of amyloid precursor protein (APP) in the brain. In APPNL-F mice, APP gene was humanized and contains two familial AD mutations, and APP-unlike other mouse models of AD-is driven by the endogenous mouse APP promoter. Similar to people without apparent cognitive dysfunction but with heavy Aß plaque load, we found no significant decline in the working memory of adult APPNL-F mice, but these mice showed decline in the expression of normal anxiety. Using immunohistochemistry and 3D block-face scanning electron microscopy, we found no changes in GABAA receptor positivity and size of somatic and dendritic synapses of hippocampal interneurons. We did not find alterations in the level of expression of perineuronal nets around parvalbumin (PV) interneurons or in the density of PV- or somatostatin-positive hippocampal interneurons. However, in contrast to other investigated cell types, PV interneuron axons were occasionally mildly dystrophic around Aß plaques, and the synapses of PV-positive axon initial segment (AIS)-targeting interneurons were significantly enlarged. Our results suggest that PV interneurons are highly resistant to amyloidosis in APPNL-F mice and amyloid-induced increase in hippocampal pyramidal cell excitability may be compensated by PV-positive AIS-targeting cells. Mechanisms that make PV neurons more resilient could therefore be exploited in the treatment of AD for mitigating Aß-related inflammatory effects on neurons.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Hipocampo/metabolismo , Interneurônios/metabolismo , Mutação , Rede Nervosa/metabolismo , Fragmentos de Peptídeos/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Animais , Axônios/metabolismo , Axônios/patologia , Hipocampo/patologia , Humanos , Interneurônios/patologia , Memória de Curto Prazo , Camundongos , Camundongos Transgênicos , Rede Nervosa/patologia , Fragmentos de Peptídeos/genética , Células Piramidais/metabolismo , Células Piramidais/patologia , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo
18.
Proc Natl Acad Sci U S A ; 117(19): 10322-10328, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32345723

RESUMO

Atomistic description of protein fibril formation has been elusive due to the complexity and long time scales of the conformational search. Here, we develop a multiscale approach combining numerous atomistic simulations in explicit solvent to construct Markov State Models (MSMs) of fibril growth. The search for the in-register fully bound fibril state is modeled as a random walk on a rugged two-dimensional energy landscape defined by ß-sheet alignment and hydrogen-bonding states, whereas transitions involving states without hydrogen bonds are derived from kinetic clustering. The reversible association/dissociation of an incoming peptide and overall growth kinetics are then computed from MSM simulations. This approach is applied to derive a parameter-free, comprehensive description of fibril elongation of Aß16-22 and how it is modulated by phenylalanine-to-cyclohexylalanine (CHA) mutations. The trajectories show an aggregation mechanism in which the peptide spends most of its time trapped in misregistered ß-sheet states connected by weakly bound states twith short lifetimes. Our results recapitulate the experimental observation that mutants CHA19 and CHA1920 accelerate fibril elongation but have a relatively minor effect on the critical concentration for fibril growth. Importantly, the kinetic consequences of mutations arise from cumulative effects of perturbing the network of productive and nonproductive pathways of fibril growth. This is consistent with the expectation that nonfunctional states will not have evolved efficient folding pathways and, therefore, will require a random search of configuration space. This study highlights the importance of describing the complete energy landscape when studying the elongation mechanism and kinetics of protein fibrils.


Assuntos
Peptídeos beta-Amiloides/química , Amiloide/química , Mutação , Fragmentos de Peptídeos/química , Fenilalanina/análogos & derivados , Fenilalanina/genética , Peptídeos beta-Amiloides/genética , Simulação por Computador , Humanos , Ligação de Hidrogênio , Cinética , Modelos Moleculares , Fragmentos de Peptídeos/genética , Estrutura Secundária de Proteína , Termodinâmica
19.
Neurobiol Aging ; 91: 66-75, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32224066

RESUMO

Cognitive impairments and circadian rhythm disorders are the main clinical manifestations of Alzheimer's disease (AD). Orexin has been reported as abnormally elevated in the cerebrospinal fluid of AD patients, accompanied with cognitive impairments. Our recent research revealed that suvorexant, a dual orexin receptor antagonist, could improve behavioral circadian rhythm disorders in 9-month-old APP/PS1 mice. Here we further observed whether suvorexant could ameliorate the cognitive decline in APP/PS1 mice by using behavioral tests, and investigated the possible mechanisms by in vivo electrophysiological recording, western blot, and immunochemistry. The results showed that suvorexant treatment effectively ameliorated the cognitive impairments, alleviated in vivo hippocampal long-term potentiation suppression, restored the circadian phosphorylated CREB expression in the hippocampus, and reduced amyloid-ß protein deposition in the hippocampus and cortex in APP/PS1 mice. These results indicate that the neuroprotective effects of suvorexant against AD are involved in the reduction of amyloid-ß plaques, improvement of synaptic plasticity, and circadian expression of phosphorylated CREB, suggesting that suvorexant could be beneficial to the prevention and treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Azepinas/farmacologia , Azepinas/uso terapêutico , Transtornos Cronobiológicos/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Neuroprostanos , Antagonistas dos Receptores de Orexina , Triazóis/farmacologia , Triazóis/uso terapêutico , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/complicações , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Transtornos Cronobiológicos/etiologia , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/etiologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Potenciação de Longa Duração/efeitos dos fármacos , Camundongos Transgênicos , Plasticidade Neuronal/efeitos dos fármacos , Orexinas/líquido cefalorraquidiano
20.
Biochim Biophys Acta Biomembr ; 1862(8): 183233, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32142821

RESUMO

It is widely accepted that the abnormal self-association of amyloid ß-protein (Aß) is central to the pathogenesis of Alzheimer's disease, the most common form of dementia. Accumulating evidence, both in vivo and in vitro, suggests that the binding of Aß to gangliosides, especially monosialoganglioside GM1, plays an important role in the aggregation of Aß. This review summarizes the molecular details of the binding of Aß to ganglioside-containing membranes and subsequent structural changes, as revealed by liposomal and cellular studies. Furthermore, mechanisms of cytotoxicity by aggregated Aß are also discussed.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Gangliosídeo G(M1)/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Gangliosídeo G(M1)/metabolismo , Humanos , Lipossomos/química , Microdomínios da Membrana/metabolismo , Microdomínios da Membrana/ultraestrutura , Ligação Proteica/efeitos dos fármacos
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