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1.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 3557-3560, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018771

RESUMO

Anodal transcranial direct current stimulation (AtDCS) can improve memory and cognitive dysfunction in patients with Alzheimer's disease (AD), which has been proven in basic and clinical studies. Intervention of AD in preclinical stage is important to prevent progression of AD in the aging society. At the same time, there is increasing evidence that a close link exists between cerebrovascular dysfunction and AD disease. Here we investigated the changes of local cerebral blood microcirculation in preclinical AD mouse model after AtDCS based on the previous studies. Twenty-four 6-month-old male APP/PS1 double transgenic mice were randomly divided into three groups: a model group (AD), a model sham stimulation (ADST) group and a model stimulation group (ATD). Eight 6-month-old male C57 wild-type mice served as a control group (CTL). Mice in the ATD group received 10 AtDCS sessions. Two months after the end of AtDCS in the ATD group, the microcirculation parameters of the frontal cortex of the mice in each group, including cerebral blood flow (CBF), blood flow velocity (Velo), oxygen saturation (SO2) and relative hemoglobin content (rHb), were obtained by the non-invasive laser-Doppler spectrophotometry system "Oxygen-to-See (O2C)". The results showed that AtDCS increased CBF, Velo and SO2, and reduce rHb in APP/PS1 double transgenic mice at the preclinical stage of AD.Clinical Relevance-This shows the positive effect of AtDCS on preclinical AD in cerebrovascular function, and provides effective basic research facts for AtDCS to intervene and delay the clinical application of AD disease.


Assuntos
Doença de Alzheimer , Estimulação Transcraniana por Corrente Contínua , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Criança , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microcirculação , Dados Preliminares , Presenilina-1/genética
3.
Nat Commun ; 11(1): 4799, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968074

RESUMO

Genetic association studies have identified 44 common genome-wide significant risk loci for late-onset Alzheimer's disease (LOAD). However, LOAD genetic architecture and prediction are unclear. Here we estimate the optimal P-threshold (Poptimal) of a genetic risk score (GRS) for prediction of LOAD in three independent datasets comprising 676 cases and 35,675 family history proxy cases. We show that the discriminative ability of GRS in LOAD prediction is maximised when selecting a small number of SNPs. Both simulation results and direct estimation indicate that the number of causal common SNPs for LOAD may be less than 100, suggesting LOAD is more oligogenic than polygenic. The best GRS explains approximately 75% of SNP-heritability, and individuals in the top decile of GRS have ten-fold increased odds when compared to those in the bottom decile. In addition, 14 variants are identified that contribute to both LOAD risk and age at onset of LOAD.


Assuntos
Doença de Alzheimer/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Adulto , Idade de Início , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
4.
Nat Commun ; 11(1): 4727, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32948752

RESUMO

The apolipoprotein E (APOE) gene contains both the major common risk variant for late onset Alzheimer's disease (AD), e4, and the major neuroprotective variant, e2. Here we examine the association of APOE e2 with multiple neurodegenerative pathologies, leveraging the NACC v. 10 database of 1557 brains that included 130 e2 carriers and 679 e4 carriers in order to examine potential neuroprotective effects. For AD-related pathologies of amyloid plaques and Braak stage, e2 had large and highly significant protective effects contrasted with e3/e3 and e4 carriers with odds ratios of about 0.50 for e3 contrasts and 0.10 for e4 contrasts. When we separately examined e2/e4 carriers, risk for AD pathologies was similar to that of e4 carriers, not e2 carriers. For multiple fronto-temporal lobar pathologies and tauopathies, e2 was not significantly associated with pathology. In sum, we found that e2 was associated with large but circumscribed protective effects.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Apolipoproteína E2/genética , Apolipoproteína E2/metabolismo , Genótipo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Encéfalo/metabolismo , Feminino , Degeneração Lobar Frontotemporal/metabolismo , Humanos , Modelos Logísticos , Masculino , Placa Amiloide/patologia , Tauopatias/metabolismo , alfa-Sinucleína/metabolismo
5.
BMC Bioinformatics ; 21(1): 377, 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32883200

RESUMO

BACKGROUND: A large number of experimental studies show that the mutation and regulation of long non-coding RNAs (lncRNAs) are associated with various human diseases. Accurate prediction of lncRNA-disease associations can provide a new perspective for the diagnosis and treatment of diseases. The main function of many lncRNAs is still unclear and using traditional experiments to detect lncRNA-disease associations is time-consuming. RESULTS: In this paper, we develop a novel and effective method for the prediction of lncRNA-disease associations using network feature similarity and gradient boosting (LDNFSGB). In LDNFSGB, we first construct a comprehensive feature vector to effectively extract the global and local information of lncRNAs and diseases through considering the disease semantic similarity (DISSS), the lncRNA function similarity (LNCFS), the lncRNA Gaussian interaction profile kernel similarity (LNCGS), the disease Gaussian interaction profile kernel similarity (DISGS), and the lncRNA-disease interaction (LNCDIS). Particularly, two methods are used to calculate the DISSS (LNCFS) for considering the local and global information of disease semantics (lncRNA functions) respectively. An autoencoder is then used to reduce the dimensionality of the feature vector to obtain the optimal feature parameter from the original feature set. Furthermore, we employ the gradient boosting algorithm to obtain the lncRNA-disease association prediction. CONCLUSIONS: In this study, hold-out, leave-one-out cross-validation, and ten-fold cross-validation methods are implemented on three publicly available datasets to evaluate the performance of LDNFSGB. Extensive experiments show that LDNFSGB dramatically outperforms other state-of-the-art methods. The case studies on six diseases, including cancers and non-cancers, further demonstrate the effectiveness of our method in real-world applications.


Assuntos
Algoritmos , Neoplasias/patologia , RNA Longo não Codificante/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Área Sob a Curva , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Humanos , Neoplasias/genética , RNA Longo não Codificante/genética , Curva ROC
6.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 49(4): 487-499, 2020 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-32985163

RESUMO

Alzheimer's disease (AD) is an aging-related neurodegenerative disease and is associated with the accumulation of amyloid-ß (Aß) peptides in patient brains. AD can be classified into the familial type and sporadic type. Presenilin-1 (PS1) is the major risk gene for familial AD (fAD) because its mutations comprised over 80%of the total mutations causing fAD. PS1 is the catalytic subunit of the enzyme γ-secretase, which is responsible for the proteolytic cleavage of amyloid precursor protein (APP) to produce Aß. Although novel fAD-causing mutations in PS1 are being reported increasingly, the molecular mechanisms underlying how these mutations induce fAD remain elusive. Since over 90%of the fAD-causing mutations in PS1 leads to a reduction of γ-secretase activity, the PS1 loss-of-function mutation hypothesis has been emerged, which suggests that the loss of PS1 functions may be the root cause of AD. Recently, increasing number of evidence supports this hypothesis. First, PS1 loss-of-function mutations increase the production of long-length Aß by disturbing the cleavage sites of γ-secretase APP, thereby increasing the ratio of Aß42/Aß40; Second, PS1 loss-of-function mutations dysregulate endoplasmic reticulum calcium homeostasis in neurons; Third, PS1 loss-of-function mutations inhibit the autophagy activity of neurons, resulting in the abnormal accumulation of cleaved products from APP; Fourth, PS1 loss-of-function mutations alter the endocytosis and transcytosis processes in neurons, leading to neuratrophy; Fifth, PS1 loss-of-function mutations activate brain immune cells (astrocytes and microglia), which mount a strong neuroinflammation response; Last, PS1 loss-of-function mutations reduce the rates of glycolysis and the production of lactic acid, disrupting the balance of neuronal energy supply. In this article we summary the research progress on the PS1 loss-of-function hypothesis and pose several topics which would guide studies of this field in future.


Assuntos
Doença de Alzheimer , Mutação , Presenilina-1 , Doença de Alzheimer/genética , Humanos , Presenilina-1/genética
7.
PLoS Biol ; 18(8): e3000851, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32822389

RESUMO

High levels of the amyloid-beta (Aß) peptide have been shown to disrupt neuronal function and induce hyperexcitability, but it is unclear what effects Aß-associated hyperexcitability may have on tauopathy pathogenesis or propagation in vivo. Using a novel transgenic mouse line to model the impact of human APP (hAPP)/Aß accumulation on tauopathy in the entorhinal cortex-hippocampal (EC-HIPP) network, we demonstrate that hAPP overexpression aggravates EC-Tau aggregation and accelerates pathological tau spread into the hippocampus. In vivo recordings revealed a strong role for hAPP/Aß, but not tau, in the emergence of EC neuronal hyperactivity and impaired theta rhythmicity. Chronic chemogenetic attenuation of EC neuronal hyperactivity led to reduced hAPP/Aß accumulation and reduced pathological tau spread into downstream hippocampus. These data strongly support the hypothesis that in Alzheimer's disease (AD), Aß-associated hyperactivity accelerates the progression of pathological tau along vulnerable neuronal circuits, and demonstrates the utility of chronic, neuromodulatory approaches in ameliorating AD pathology in vivo.


Assuntos
Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Córtex Entorrinal/metabolismo , Tauopatias/genética , Proteínas tau/genética , Potenciais de Ação/fisiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/terapia , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Dependovirus/genética , Dependovirus/metabolismo , Modelos Animais de Doenças , Eletrodos Implantados , Córtex Entorrinal/patologia , Feminino , Regulação da Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/metabolismo , Neurônios/patologia , Agregados Proteicos , Técnicas Estereotáxicas , Tauopatias/metabolismo , Tauopatias/patologia , Tauopatias/terapia , Ritmo Teta/fisiologia , Transdução Genética , Transgenes , Proteínas tau/metabolismo
8.
PLoS One ; 15(8): e0235691, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32857763

RESUMO

Exercise exerts a beneficial effect on the major pathological and clinical symptoms associated with Alzheimer's disease in humans and mouse models of the disease. While numerous mechanisms for such benefits from exercise have been proposed, a clear understanding of the causal links remains elusive. Recent studies also suggest that cerebral blood flow in the brain of both Alzheimer's patients and mouse models of the disease is decreased and that the cognitive symptoms can be improved when blood flow is restored. We therefore hypothesized that the mitigating effect of exercise on the development and progression of Alzheimer's disease may be mediated through an increase in the otherwise reduced brain blood flow. To test this idea, we performed a pilot study to examine the impact of three months of voluntary wheel running in a small cohort of ~1-year-old APP/PS1 mice on short-term memory function, brain inflammation, amyloid deposition, and baseline cerebral blood flow. Our findings that exercise led to a trend toward improved spatial short-term memory, reduced brain inflammation, markedly increased neurogenesis in the dentate gyrus, and a reduction in hippocampal amyloid-beta deposits are consistent with other reports on the impact of exercise on the progression of Alzheimer's related symptoms in mouse models. Notably, we did not observe any impact of wheel running on overall baseline blood flow nor on the incidence of non-flowing capillaries, a mechanism we recently identified as one contributing factor to cerebral blood flow deficits in mouse models of Alzheimer's disease. Overall, our findings add to the emerging picture of differential effects of exercise on cognition and blood flow in Alzheimer's disease pathology by showing that capillary stalling is not decreased following exercise.


Assuntos
Doença de Alzheimer/fisiopatologia , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/irrigação sanguínea , Terapia por Exercício , Presenilina-1/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/terapia , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Circulação Cerebrovascular , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Mutação , Neurogênese , Condicionamento Físico Animal , Projetos Piloto , Presenilina-1/genética , Transgenes
9.
PLoS Med ; 17(8): e1003289, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32817639

RESUMO

BACKGROUND: The ε4 allele of apolipoprotein E (APOE) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association between APOE genotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of ß-amyloid peptide (A, ß-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD. METHODS AND FINDINGS: This case-control study included 1,593 white AD cases (55.4% women; mean age 72.8 [range = 44-96] years) with abnormal values of CSF biomarkers from nine European memory clinics and the American Alzheimer's Disease Neuroimaging Initiative (ADNI) study. A total of 11,723 dementia-free controls (47.1% women; mean age 65.6 [range = 44-94] years) were drawn from two longitudinal cohort studies (Whitehall II and Three-City), in which incident cases of dementia over the follow-up were excluded from the control population. Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were determined, overall and by 5-year age categories. In total, 63.4% of patients with AD and 22.6% of population controls carried at least one APOE ε4 allele. Compared with non-ε4 carriers, heterozygous ε4 carriers had a 4.6 (95% confidence interval 4.1-5.2; p < 0.001) and ε4/ε4 homozygotes a 25.4 (20.4-31.2; p < 0.001) higher OR of AD in unadjusted analysis. This association was modified by age (p for interaction < 0.001). The PAF associated with carrying at least one ε4 allele was greatest in the 65-70 age group (69.7%) and weaker before 55 years (14.2%) and after 85 years (22.6%). The protective effect of APOE ε2 allele for AD was unaffected by age. Main study limitations are that analyses were based on white individuals and AD cases were drawn from memory centers, which may not be representative of the general population of patients with AD. CONCLUSIONS: In this study, we found that AD diagnosis based on biomarkers was associated with APOE ε4 carrier status, with a higher OR than previously reported from studies based on only clinical AD criteria. This association differs according to age, with the strongest effect at 65-70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE ε4 at the population level.


Assuntos
Envelhecimento/líquido cefalorraquidiano , Envelhecimento/genética , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Apolipoproteína E4/líquido cefalorraquidiano , Apolipoproteína E4/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
10.
Am J Hum Genet ; 107(3): 445-460, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32750315

RESUMO

Tandem repeats are proposed to contribute to human-specific traits, and more than 40 tandem repeat expansions are known to cause neurological disease. Here, we characterize a human-specific 69 bp variable number tandem repeat (VNTR) in the last intron of WDR7, which exhibits striking variability in both copy number and nucleotide composition, as revealed by long-read sequencing. In addition, greater repeat copy number is significantly enriched in three independent cohorts of individuals with sporadic amyotrophic lateral sclerosis (ALS). Each unit of the repeat forms a stem-loop structure with the potential to produce microRNAs, and the repeat RNA can aggregate when expressed in cells. We leveraged its remarkable sequence variability to align the repeat in 288 samples and uncover its mechanism of expansion. We found that the repeat expands in the 3'-5' direction, in groups of repeat units divisible by two. The expansion patterns we observed were consistent with duplication events, and a replication error called template switching. We also observed that the VNTR is expanded in both Denisovan and Neanderthal genomes but is fixed at one copy or fewer in non-human primates. Evaluating the repeat in 1000 Genomes Project samples reveals that some repeat segments are solely present or absent in certain geographic populations. The large size of the repeat unit in this VNTR, along with our multiplexed sequencing strategy, provides an unprecedented opportunity to study mechanisms of repeat expansion, and a framework for evaluating the roles of VNTRs in human evolution and disease.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Esclerose Amiotrófica Lateral/genética , Evolução Molecular , Sequências de Repetição em Tandem/genética , Idoso , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Esclerose Amiotrófica Lateral/patologia , Expansão das Repetições de DNA/genética , Feminino , Regulação da Expressão Gênica/genética , Humanos , Masculino , Repetições Minissatélites/genética , Fenótipo , Especificidade da Espécie
11.
Nat Commun ; 11(1): 3960, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769986

RESUMO

Sporadic Creutzfeldt-Jakob disease (sCJD) presents as a rapidly progressive dementia which is usually fatal within six months. No clinical blood tests are available for diagnosis or disease monitoring. Here, we profile blood microRNA (miRNA) expression in sCJD. Sequencing of 57 sCJD patients, and healthy controls reveals differential expression of hsa-let-7i-5p, hsa-miR-16-5p, hsa-miR-93-5p and hsa-miR-106b-3p. Downregulation of hsa-let-7i-5p, hsa-miR-16-5p and hsa-miR-93-5p replicates in an independent cohort using quantitative PCR, with concomitant upregulation of four mRNA targets. Absence of correlation in cross-sectional analysis with clinical phenotypes parallels the lack of association between rate of decline in miRNA expression, and rate of disease progression in a longitudinal cohort of samples from 21 patients. Finally, the miRNA signature shows a high level of accuracy in discriminating sCJD from Alzheimer's disease. These findings highlight molecular alterations in the periphery in sCJD which provide information about differential diagnosis and improve mechanistic understanding of human prion diseases.


Assuntos
Síndrome de Creutzfeldt-Jakob/sangue , Síndrome de Creutzfeldt-Jakob/genética , Perfilação da Expressão Gênica , MicroRNAs/sangue , MicroRNAs/genética , Idoso , Doença de Alzheimer/genética , Biomarcadores/sangue , Estudos de Coortes , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/patologia , Progressão da Doença , Feminino , Regulação da Expressão Gênica , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Curva ROC , Reprodutibilidade dos Testes
12.
PLoS Comput Biol ; 16(7): e1008099, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32706788

RESUMO

Next-generation sequencing (NGS) technology has become a powerful tool for dissecting the molecular and pathological signatures of a variety of human diseases. However, the limited availability of biological samples from different disease stages is a major hurdle in studying disease progressions and identifying early pathological changes. Deep learning techniques have recently begun to be applied to analyze NGS data and thereby predict the progression of biological processes. In this study, we applied a deep learning technique called generative adversarial networks (GANs) to predict the molecular progress of Alzheimer's disease (AD). We successfully applied GANs to analyze RNA-seq data from a 5xFAD mouse model of AD, which recapitulates major AD features of massive amyloid-ß (Aß) accumulation in the brain. We examined how the generator is featured to have specific-sample generation and biological gene association. Based on the above observations, we suggested virtual disease progress by latent space interpolation to yield the transition curves of various genes with pathological changes from normal to AD state. By performing pathway analysis based on the transition curve patterns, we identified several pathological processes with progressive changes, such as inflammatory systems and synapse functions, which have previously been demonstrated to be involved in the pathogenesis of AD. Interestingly, our analysis indicates that alteration of cholesterol biosynthesis begins at a very early stage of AD, suggesting that it is the first effect to mediate the cholesterol metabolism of AD downstream of Aß accumulation. Here, we suggest that GANs are a useful tool to study disease progression, leading to the identification of early pathological signatures.


Assuntos
Doença de Alzheimer/fisiopatologia , RNA-Seq , Algoritmos , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/metabolismo , Córtex Cerebral/metabolismo , Colesterol/metabolismo , Análise por Conglomerados , Aprendizado Profundo , Modelos Animais de Doenças , Progressão da Doença , Humanos , Inflamação , Camundongos , Modelos Genéticos , RNA Mensageiro/metabolismo , Sinapses/metabolismo , Lobo Temporal/metabolismo , Sequenciamento Completo do Exoma
13.
Mol Cell Biol ; 40(19)2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32690545

RESUMO

Neuronal ceroid lipofuscinosis (NCL) is one of the most prevalent neurodegenerative disorders of early life, Parkinson's disease (PD) is the most common neurodegenerative disorder of midlife, while Alzheimer's disease (AD) is the most common neurodegenerative disorder of late life. While they are phenotypically distinct, recent studies suggest that they share a biological pathway, retromer-dependent endosomal trafficking. A retromer is a multimodular protein assembly critical for sorting and trafficking cargo out of the endosome. As a lysosomal storage disease, all 13 of NCL's causative genes affect endolysosomal function, and at least four have been directly linked to retromer. PD has several known causative genes, with one directly linked to retromer and others causing endolysosomal dysfunction. AD has over 25 causative genes/risk factors, with several of them linked to retromer or endosomal trafficking dysfunction. In this article, we summarize the emerging evidence on the association of genes causing NCL with retromer function and endosomal trafficking, review the recent evidence linking NCL genes to AD, and discuss how NCL, AD, and PD converge on a shared molecular pathway. We also discuss this pathway's role in microglia and neurons, cell populations which are critical to proper brain homeostasis and whose dysfunction plays a key role in neurodegeneration.


Assuntos
Doença de Alzheimer/metabolismo , Endossomos/metabolismo , Lipofuscinoses Ceroides Neuronais/genética , Lipofuscinoses Ceroides Neuronais/metabolismo , Doença de Parkinson/metabolismo , Doença de Alzheimer/genética , Animais , Transporte Biológico , Humanos , Doença de Parkinson/genética , Presenilina-1/genética , Presenilina-1/metabolismo
14.
Nat Rev Drug Discov ; 19(7): 447-462, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32612262

RESUMO

A large number of mouse models have been engineered, characterized and used to advance biomedical research in Alzheimer disease (AD). Early models simply damaged the rodent brain through toxins or lesions. Later, the spread of genetic engineering technology enabled investigators to develop models of familial AD by overexpressing human genes such as those encoding amyloid precursor protein (APP) or presenilins (PSEN1 or PSEN2) carrying mutations linked to early-onset AD. Recently, more complex models have sought to explore the impact of multiple genetic risk factors in the context of different biological challenges. Although none of these models has proven to be a fully faithful reproduction of the human disease, models remain essential as tools to improve our understanding of AD biology, conduct thorough pharmacokinetic and pharmacodynamic analyses, discover translatable biomarkers and evaluate specific therapeutic approaches. To realize the full potential of animal models as new technologies and knowledge become available, it is critical to define an optimal strategy for their use. Here, we review progress and challenges in the use of AD mouse models, highlight emerging scientific innovations in model development, and introduce a conceptual framework for use of preclinical models for therapeutic development.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Modelos Animais de Doenças , Desenvolvimento de Medicamentos/métodos , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Animais , Biomarcadores/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Predisposição Genética para Doença , Humanos , Camundongos , Mutação , Fatores de Risco
15.
PLoS Genet ; 16(7): e1008903, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32678846

RESUMO

Genome wide association studies (GWAS) of human diseases have generally identified many loci associated with risk with relatively small effect sizes. The omnigenic model attempts to explain this observation by suggesting that diseases can be thought of as networks, where genes with direct involvement in disease-relevant biological pathways are named 'core genes', while peripheral genes influence disease risk via their interactions or regulatory effects on core genes. Here, we demonstrate a method for identifying candidate core genes solely from genes in or near disease-associated SNPs (GWAS hits) in conjunction with protein-protein interaction network data. Applied to 1,381 GWAS studies from 5 ancestries, we identify a total of 1,865 candidate core genes in 343 GWAS studies. Our analysis identifies several well-known disease-related genes that are not identified by GWAS, including BRCA1 in Breast Cancer, Amyloid Precursor Protein (APP) in Alzheimer's Disease, INS in A1C measurement and Type 2 Diabetes, and PCSK9 in LDL cholesterol, amongst others. Notably candidate core genes are preferentially enriched for disease relevance over GWAS hits and are enriched for both Clinvar pathogenic variants and known drug targets-consistent with the predictions of the omnigenic model. We subsequently use parent term annotations provided by the GWAS catalog, to merge related GWAS studies and identify candidate core genes in over-arching disease processes such as cancer-where we identify 109 candidate core genes.


Assuntos
Doença de Alzheimer/genética , Neoplasias da Mama/genética , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Mapas de Interação de Proteínas/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Proteína BRCA1/genética , Neoplasias da Mama/patologia , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Insulina/genética , Polimorfismo de Nucleotídeo Único/genética , Pró-Proteína Convertase 9/genética , Fatores de Risco
16.
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
17.
Neurology ; 95(10): e1312-e1321, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32611637

RESUMO

OBJECTIVE: To determine whether performance on the Free and Cued Selective Reminding Test (FCSRT) is associated with PET in vivo markers of brain pathology and whether it can distinguish those who will develop dementia later in life due to autosomal-dominant Alzheimer disease (AD) from age-matched controls. METHODS: Twenty-four cognitively unimpaired Presenilin-1 E280A carriers (mean age 36 years) and 28 noncarriers (mean age 37 years) underwent Pittsburg compound B-PET (amyloid), flortaucipir-PET (tau), and cognitive testing, including the FCSRT (immediate and delayed free and cued recall scores). Linear regressions were used to examine the relationships among FCSRT scores, age, mean cortical amyloid, and regional tau burden. RESULTS: Free and total recall scores did not differ between cognitively unimpaired mutation carriers and noncarriers. Greater age predicted lower free recall and delayed free and total recall scores in carriers. In cognitively impaired carriers, delayed free recall predicted greater amyloid burden and entorhinal tau, while worse immediate free recall scores predicted greater tau in the inferior temporal and entorhinal cortices. In turn, in all carriers, lower free and total recall scores predicted greater amyloid and regional tau pathology. CONCLUSIONS: FCSRT scores were associated with in vivo markers of AD-related pathology in cognitively unimpaired individuals genetically determined to develop dementia. Difficulties on free recall, particularly delayed recall, were evident earlier in the disease trajectory, while difficulties on cued recall were seen only as carriers neared the onset of dementia, consistent with the pathologic progression of the disease. Findings suggest that the FCSRT can be a useful measure to track disease progression in AD.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Encéfalo/patologia , Rememoração Mental , Presenilina-1/genética , Adulto , Feminino , Predisposição Genética para Doença/genética , Heterozigoto , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Adulto Jovem
18.
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
19.
PLoS Genet ; 16(6): e1008775, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32492070

RESUMO

Late-Onset Alzheimer's disease (LOAD) is a common, complex genetic disorder well-known for its heterogeneous pathology. The genetic heterogeneity underlying common, complex diseases poses a major challenge for targeted therapies and the identification of novel disease-associated variants. Case-control approaches are often limited to examining a specific outcome in a group of heterogenous patients with different clinical characteristics. Here, we developed a novel approach to define relevant transcriptomic endophenotypes and stratify decedents based on molecular profiles in three independent human LOAD cohorts. By integrating post-mortem brain gene co-expression data from 2114 human samples with LOAD, we developed a novel quantitative, composite phenotype that can better account for the heterogeneity in genetic architecture underlying the disease. We used iterative weighted gene co-expression network analysis (WGCNA) to reduce data dimensionality and to isolate gene sets that are highly co-expressed within disease subtypes and represent specific molecular pathways. We then performed single variant association testing using whole genome-sequencing data for the novel composite phenotype in order to identify genetic loci that contribute to disease heterogeneity. Distinct LOAD subtypes were identified for all three study cohorts (two in ROSMAP, three in Mayo Clinic, and two in Mount Sinai Brain Bank). Single variant association analysis identified a genome-wide significant variant in TMEM106B (p-value < 5×10-8, rs1990620G) in the ROSMAP cohort that confers protection from the inflammatory LOAD subtype. Taken together, our novel approach can be used to stratify LOAD into distinct molecular subtypes based on affected disease pathways.


Assuntos
Doença de Alzheimer/genética , Genes Modificadores , Transcriptoma , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Feminino , Perfilação da Expressão Gênica/métodos , Heterogeneidade Genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único
20.
J Pharmacol Sci ; 143(4): 290-299, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32507685

RESUMO

The pathophysiological roles of astrocytes in the reactive state are thought to have important significance in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). However, the detailed mechanisms underlying the transition of astrocytes from the resting state to the reactive state during neurodegenerative disease largely remain to be defined. Here, we investigated the pathways involved in activating astrocytes from the resting state to the reactive state in primary cultured astrocytes treated with oligomeric Aß and in the hippocampus of 5XFAD mice. Treatment with oligomeric Aß induced an increase in reactive astrocytes, as assessed by the protein level of glial fibrillary acidic protein (GFAP) and this increase was caused by STAT3 phosphorylation in primary cultured astrocytes. The administration of Stattic, an inhibitor of STAT3, rescued the activation of astrocytes in primary cultured astrocytes and in the hippocampus of 6-month-old 5XFAD mice as well as impairments in learning and memory. Collectively, these results demonstrated that reactive astrocytes in the AD brain are induced via STAT3 and the impairments in learning and memory observed in 5XFAD mice are rescued by STAT3 inhibition, suggesting that the inhibition of STAT3 phosphorylation in astrocytes may be a novel therapeutic target for cognitive impairment in AD.


Assuntos
Doença de Alzheimer/genética , Inativação Gênica , Fator de Transcrição STAT3 , Doença de Alzheimer/terapia , Animais , Astrócitos/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Camundongos Transgênicos , Terapia de Alvo Molecular , Fosforilação
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