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1.
Adv Exp Med Biol ; 1175: 273-324, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31583592

RESUMO

Alzheimer's disease is the most common cause of dementia. Cellular changes in the brains of the patients suffering from Alzheimer's disease occur well in advance of the clinical symptoms. At the cellular level, the most dramatic is a demise of neurones. As astroglial cells carry out homeostatic functions of the brain, it is certain that these cells are at least in part a cause of Alzheimer's disease. Historically, Alois Alzheimer himself has recognised this at the dawn of the disease description. However, the role of astroglia in this disease has been understudied. In this chapter, we summarise the various aspects of glial contribution to this disease and outline the potential of using these cells in prevention (exercise and environmental enrichment) and intervention of this devastating disease.


Assuntos
Doença de Alzheimer/fisiopatologia , Astrócitos/citologia , Neuroglia/citologia , Encéfalo/fisiopatologia , Humanos
2.
Adv Exp Med Biol ; 1175: 325-333, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31583593

RESUMO

Oligodendrocytes form the myelin that ensheaths CNS axons, which is essential for rapid neuronal signalling and underpins the massive computing power of the human brain. Oligodendrocytes and myelin also provide metabolic and trophic support for axons and their disruption results in axonal demise and neurodegeneration, which are key features of Alzheimer's disease (AD). Notably, the brain has a remarkable capacity for regenerating oligodendrocytes, which is the function of adult oligodendrocyte progenitor cells (OPCs) or NG2-glia. White matter loss is often among the earliest brain changes in AD, preceding the tangles and plaques that characterize neuronal deficits. The underlying causes of myelin loss include oxidative stress, neuroinflammation and excitotoxicity, associated with accumulation of Aß and tau hyperphosphorylation, pathological hallmarks of AD. Moreover, there is evidence that NG2-glia are disrupted in AD, which may be associated with disruption of synaptic signalling. This has led to the hypothesis that a vicious cycle of myelin loss and failure of regeneration from NG2-glia plays a key role in AD. Therapies that target NG2-glia are likely to have positive effects on myelination and neuroprotection in AD.


Assuntos
Doença de Alzheimer/fisiopatologia , Bainha de Mielina/patologia , Oligodendroglia/citologia , Axônios , Doenças Desmielinizantes/fisiopatologia , Humanos
3.
Adv Exp Med Biol ; 1175: 383-405, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31583596

RESUMO

Despite over a century of research into Alzheimer's disease (AD), progress in understanding the complex aetiology has been hindered, in part, by a lack of human, disease relevant, cellular models, reflected in an inability to translate results from animal studies to successful human therapies. Induced pluripotent stem cell (iPSC) technology, in which somatic cells are reprogrammed to pluripotent stem cells, creates an ideal physiologically relevant model as they maintain the genetic identity of the donor. These iPSCs can self-renew indefinitely in vitro and have the capacity to differentiate into any cell type, opening up new discovery and therapeutic opportunities. Despite a plethora of publications indicating the generation and utility of iPSC-derived neurones for disease modelling to date, in comparison only a limited number of studies have described generation of enriched astroglia from patients with early- or late-stage onset of AD. We recently reported that iPSC-astroglia derived from these patients are capable of mimicking a wide variety of deficits in homeostatic molecular cascades, intimately associated with AD, that are routinely observed in vivo. This review examines the opportunities and limitations of this innovative technology in the context of AD modelling and uses for preclinical discovery to improve our success for an efficacious therapeutic outcome.


Assuntos
Doença de Alzheimer , Astrócitos/citologia , Células-Tronco Pluripotentes Induzidas/citologia , Animais , Humanos , Neurônios
4.
Brain Nerve ; 71(10): 1039-1051, 2019 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-31588048

RESUMO

Dementia is a leading cause of death in many countries. Late-onset Alzheimer's disease (LOAD) is the most common form of dementia, with approximately 35 million affected people. LOAD shows a high heritability (h2) of 58-79%. Clarifying the genetic architecture of LOAD could contribute to precision medicine. In recent years, large-scale genome-wide association studies (GWASs) and their meta-analyses with a large sample size have elucidated the disease-susceptible genes and disease-causing pathways. To date, meta-analyses of GWASs in the Caucasian population have successfully identified approximately 40 LOAD risk loci. The gene set and disease pathway analysis obtained from the results of GWASs suggested biological mechanisms involving brain immune function, lipid-related processes, tau binding proteins, and degradation of amyloid precursor proteins in the pathogenesis of LOAD. Furthermore, the exome sequencing analysis in Japanese individuals with LOAD also revealed a rare variant with a large effect of SHARPIN in LOAD susceptibility, and the variant protein possibly affects the immune response through aberrant cellular localization, which may result in attenuated NF-κB activity in the brain. These findings could provide biological and pharmaceutical approaches in precision medicine for LOAD.


Assuntos
Doença de Alzheimer/genética , Patrimônio Genético , Estudo de Associação Genômica Ampla , Predisposição Genética para Doença , Humanos , NF-kappa B/metabolismo , Ubiquitinas/genética , Proteínas tau/metabolismo
5.
Brain Nerve ; 71(10): 1053-1060, 2019 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-31588049

RESUMO

Apolipoprotein E (APOE) is reported to be a strong genetic risk factor for Alzheimer's disease (AD), broadly contributing to the AD pathologies observed in most populations. However, it is difficult to explicate these AD pathologies based only on the known functions of APOE. In this review article, we revisited the histories and functions of APOE and also reviewed its recently elucidated the pleiotropic roles in the brain.


Assuntos
Doença de Alzheimer/genética , Apolipoproteína E4/genética , Encéfalo , Humanos , Fatores de Risco
6.
Brain Nerve ; 71(10): 1071-1079, 2019 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-31588051

RESUMO

Next generation sequencing (NGS) technology has dramatically influenced the field of omics studies, such as genomics and transcriptomics. It is now possible to access a significant number of previously known and novel genomic variants through NGS. Although the effective manipulation and accurate interpretation of the inordinate amount of data may pose a considerable challenge, it enables us to identify specific genes responsible for causing or influencing the susceptibility to a plethora of diseases. Alzheimer's disease (AD) is the most common etiology of dementia in the elderly (approximately 60-70%). The current research trend of AD genetics focuses on the analysis of rare variants (allelic frequency <1%) instead of common variants (allelic frequency >1%) to identify AD-associated genes/variants. A number of genes (such as TREM2, ABCA7, SORL1) that carry rare pathogenic variants have reportedly conferred susceptibility to AD with stronger genetic risk effects (odds ratio >2.0). Here, we are going to introduce a small part of the latest many attractive findings about AD genetic researches.


Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença , Transportadores de Cassetes de Ligação de ATP/genética , Alelos , Frequência do Gene , Testes Genéticos , Genômica , Humanos , Proteínas Relacionadas a Receptor de LDL/genética , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , Receptores Imunológicos/genética
7.
Brain Nerve ; 71(10): 1081-1088, 2019 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-31588052

RESUMO

During the past 20 years, genome studies for Alzheimer's disease (AD) have elucidated the pathogenesis of AD including the amyloid hypothesis. However, clinical trials of the disease modifying drugs for AD developed based on the amyloid hypothesis have been largely unsuccessful. New genes associated with AD have been identified through comprehensive genome analyses such as genome-wide association studies and whole genome/exome sequencing using next-generation sequencers. With these efforts, new therapeutic targets to AD have been explored. This review summarizes the genetic make-up of AD in terms of both risk and protective factors from the viewpoint of novel therapeutic targets to AD.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/terapia , Testes Genéticos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Fatores de Proteção , Fatores de Risco
8.
Brain Nerve ; 71(9): 961-970, 2019 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-31506398

RESUMO

To date, all clinical trials of disease-modifying drugs for Alzheimer's disease (AD) have been unsuccessful, making investments into AD drug development very risky despite the high unmet need. Drug repositioning or repurposing approaches are relatively less expensive and more promising compared to novel drug development in AD. About 40% of clinical trials for AD currently in progress across the world use the drug repositioning method. They are expected to be a trigger for AD drug discovery that breaks the current deadlock situation. By using drugs approved for other indications, these clinical trials target dysregulated pathways of AD with different or a combination of modes of action, including anti-amyloid, anti-tau, anti-inflammatory, metabolic, neuroprotective, and neurotransmission-based approaches. In these clinical trials, cardiovascular drugs such as insulin, cilostazol, probucol, telmisartan, and dabigatran are tested for their effect on different mechanisms of AD pathology. This is in line with the recent emphasis that AD should be studied as a complex multifactorial disorder, not dominated by one dominant biological factor such as beta-amyloid, and without disregarding any relevant pathologic factor, such as vascular dysregulation. It is strongly expected that drug repositioning approaches will create a paradigm shift in treatment approaches for AD patients.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Reposicionamento de Medicamentos , Cilostazol , Dabigatrana , Humanos , Insulina , Probucol , Telmisartan
10.
Braz J Med Biol Res ; 52(8): e8443, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31365694

RESUMO

Brain-derived neurotrophic factor (BDNF) is widely expressed in the central nervous system and prolongs the survival of dopaminergic neurons in the substantia nigra. Several studies have recently investigated the association between BDNF G196A (Val66Met), a single nucleotide polymorphism influencing cognitive processes, and cognitive impairment in Parkinson's disease (PD), but with contradictory findings. Thus, this meta-analysis was performed to clarify the possible association. Relevant studies were identified by a systematic search of PubMed, Embase, and China National Knowledge Infrastructure (CNKI) databases. The strength of the association was evaluated using crude odds ratios and 95% confidence interval. Finally, six studies involving 532 cases and 802 controls were included. Our analyses suggested the G196A (Val66Met) polymorphism was significantly associated with cognitive impairment in PD, especially in Caucasian populations. In conclusion, BDNF G196A (Val66Met) is confirmed to be a risk factor for cognitive impairment in PD.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Disfunção Cognitiva/genética , Doença de Parkinson/genética , Doença de Alzheimer/complicações , Estudos de Casos e Controles , Disfunção Cognitiva/complicações , Grupo com Ancestrais do Continente Europeu , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Razão de Chances , Doença de Parkinson/complicações , Polimorfismo de Nucleotídeo Único , Fatores de Risco
11.
Zhonghua Yi Xue Za Zhi ; 99(31): 2423-2428, 2019 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-31434421

RESUMO

Objective: To compare the features of a modified WHO/UCLA AVLT performance in the cognitive normal, amnestic mild cognitive impairment (aMCI) and mild Alzheimer's disease (mild AD) patients. Method: A total of 105 cases of cognitivenormal (CN), 48 aMCI and 50 mild AD patients were included between 2016 and 2018. All subjects undertook detailed neuropsychological tests and brain MRI/CT scan. Results: The total score of five learning trials in CN, aMCI and AD groups were 53.9±6.9, 34.6±8.3 and 23.7±6.2, respectively (P<0.001). The score of 20-min delay recallwere 12.5±1.6, 4.3±3.0 and 0.6±1.0, respectively (P<0.001) in three groups. The score of cued recall were 13.0±1.4, 7.0±2.4 and 2.6±2.0, respectively (P<0.001). The score of 20-min delay recall had the largest effect sizes between CN and aMCI groups (Cohen'd=3.8, 95%CI,3.3-4.4), and CN and mild AD groups (Cohen'd=8.1, 95%CI 7.1-9.1). Cued recall had the largest effect size between aMCI and mild AD groups (Cohen'd=2.04, 95%CI 1.5-2.5). The scores of learning total score, 20-min delay recall, cued recall and recognition had the strong relationships with the scores of mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA) , but obtaining moderate relationships with Boston naming test and trail making test (TMT) and weak relationships with digit span and figure copy. Age and education had no relationship with the main indices of this modified AVLT. Conclusions: The modified WHO/UCLA AVLT is still an age and education fair test to assess memory domain function. Qualitative analysis of AVLT profiles may be useful to differentiate the CN, aMCI and mild AD in Chinese sample.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Imagem por Ressonância Magnética , Memória , Testes Neuropsicológicos
12.
Stud Health Technol Inform ; 264: 343-347, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31437942

RESUMO

Behavioral analysis for identifying changes in cognitive and physical functioning is expected to help detect dementia such as mild cognitive impairment (MCI) at an early stage. Speech and gait features have been especially recognized as behavioral biomarkers for dementia that possibly occur early in its course, including MCI. However, there are no studies investigating whether exploiting the combination of multimodal behavioral data could improve detection accuracy. In this study, we collected speech and gait behavioral data from Japanese seniors consisting of cognitively healthy adults and patients with MCI. Comparing the models using single modality behavioral data, we showed that the model using multimodal behavioral data could improve detection by up to 5.9%, achieving 82.4% accuracy (chance 55.9%). Our results suggest that the combination of multimodal behavioral features capturing different functional changes resulting from dementia might improve accuracy and help timely diagnosis at an early stage.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Marcha , Humanos , Fala
13.
Stud Health Technol Inform ; 264: 358-362, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31437945

RESUMO

Early detection of Alzheimer's disease is important for deploying interventions to prevent or slow disease progression. We propose a multi-view dependence modeling framework that integrates multiple data sources to distinguish patients at different stages of the disease. We design interpretable models that can handle heterogeneous data types including neuro-images, bio- and clinical markers, and historical and genotypical characteristics of the subjects. We learn the dependence structure from data with guidance from domain knowledge in Bayesian Networks, visualizing and quantifying the conditional probabilistic dependence among the variables. Our results indicate that the hybrid dependence models also improve prediction performance.


Assuntos
Doença de Alzheimer , Teorema de Bayes , Biomarcadores , Diagnóstico Precoce , Humanos
14.
Chem Commun (Camb) ; 55(70): 10424-10427, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31407744

RESUMO

The development of sensitive and reliable fluorescent probes for the early diagnosis of Alzheimer's disease (AD) is highly challenging and plays an important role in achieving effective treatments. Herein, we designed and synthesized an indole-based fluorophore for TTR in human plasma, an important hallmark of AD pathogenesis. This robust and simple fluorescent method allows quantification of TTR in the complex biological matrix.


Assuntos
Doença de Alzheimer/diagnóstico , Corantes Fluorescentes/química , Pré-Albumina/metabolismo , Doença de Alzheimer/sangue , Peptídeos beta-Amiloides/metabolismo , Humanos , Limite de Detecção , Espectrometria de Fluorescência
15.
Adv Exp Med Biol ; 1173: 67-104, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456206

RESUMO

Alzheimer's disease (AD) is a multifactorial neurodegenerative condition associated with pathological accumulation of amyloid plaques and with the appearance of deposit of neurofibrillary tangles. Increasing evidence suggests that disorders of metal ion metabolism in the brain are one of the risk factors for the pathogenesis of AD. Iron, one of the endogenous metal ions, involves in many important physiological activities in the brain. Iron metabolism mainly depends on iron regulatory proteins including ferritin, transferrin and transferrin receptor, hepcidin, ferroportin, lactoferrin. Abnormal iron metabolism generates hydroxyl radicals through the Fenton reaction, triggers oxidative stress reactions, damages cell lipids, protein and DNA structure and function, leads to cell death, and ultimately influences the process of ß-amyloid (Aß) misfolding and plaque aggregation. Although the results are different, in general, iron has deposition in different brain regions of AD patients, which may impair normal cognitive function and behavior. Therefore, neuroimaging changes have so far been largely attributed to focal iron deposition accompanying the plaques at preclinical stages of AD, and iron-targeted therapeutic strategies have become a new direction. Iron chelators have received a great deal of attention and have obtained good results in scientific experiments and some clinical trials. Future research will also focus on iron as an opportunity to study the mechanism of the occurrence and development of AD from the iron steady state to more fully clarify the etiology and prevention strategies.


Assuntos
Doença de Alzheimer/patologia , Encéfalo/metabolismo , Ferro/metabolismo , Peptídeos beta-Amiloides , Encéfalo/fisiopatologia , Humanos , Emaranhados Neurofibrilares/patologia , Placa Amiloide/patologia
17.
Genome Biol ; 20(1): 152, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375147

RESUMO

Jacob and Speed did not identify even a single example of a '150-gene-set' that was statistically significant at classifying Alzheimer's disease (AD) samples, or age in independent studies. We attempt to clarify the various misunderstandings, below.


Assuntos
Doença de Alzheimer , Envelhecimento Saudável , Cognição , Nível de Saúde , Humanos , RNA
18.
Science ; 365(6453): 540-541, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31395769
19.
Stud Health Technol Inform ; 264: 168-172, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31437907

RESUMO

Early detection of Alzheimer's disease (AD) has become increasingly important. Healthy monitoring technology focusing on behavioral changes is a promising approach in this vein. Among such technologies, handwriting features measured by digital tablet devices have attracted attention as potential indicators for detecting AD and mild cognitive impairment (MCI). However, previous studies have mainly investigated features in single tasks, and it remains unclear whether combining the features of multiple tasks could improve the performance of detecting AD and MCI. In this study, we investigated features in five representative tasks used in neuropsychological tests collected from 71 seniors including some diagnosed with MCI and AD. We found that our three-class classification model improved diagnosis accuracy by up to 11.3% by combining features of multiple tasks, for a final accuracy of 74.6%. We also suggested that drawing behaviors during multiple tasks might be useful for estimating disease progression simply by utilizing the labels of disease groups.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/diagnóstico , Progressão da Doença , Diagnóstico Precoce , Escrita Manual , Humanos , Testes Neuropsicológicos
20.
Cell Physiol Biochem ; 53(2): 413-428, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31415717

RESUMO

BACKGROUND/AIMS: Amyloid plaques, generated during the progression of Alzheimer's disease, cause major neurological deficits due to substantial cell toxicity and death. The underlying cause of plaque generation stems from cleavage of the amyloid precursor protein (APP) by ß-secretase (BACE1). A resulting amyloid-ß (Aß) fragment forms aggregates to produce the main constituent of a plaque. METHODS: Phage display and biopanning techniques were used to identify a 12-mer peptide that had a natural affinity for the BACE1 enzyme. The peptide was translated from phage DNA and synthetically produced. The peptide, at concentrations of 1nM, 10nM and 100nM, was used to confirm binding by direct assay. Non-specific binding to BACE2, renin and cathepsin D was tested by direct binding assay. A BACE1 activity assay was used to determine the peptide effect on cleavage of an APP substrate. Treatment of SY5Y cells with the peptide was used to determine toxicity and prevention of Aß40 and Aß42 production. RESULTS: After identification and synthetic production, the peptide exhibited a strong affinity for BACE1 at nanomolar concentrations in the direct assay. In case of non-specific binding to homologous BACE2, renin and cathepsin D, the peptide showed minor binding but was nullified when in solution with BACE1. The peptide addition to a BACE1 activity assay was able to significantly reduce the amount of substrate cleavage. SY5Y cells, when treated with the peptide, did not show any detrimental morphological changes while being able to reduce the production of natural Aß40 and Aß42. Even under stressed conditions (H2O2 treatment) where the Aß production was higher, the peptide was still able to significantly reduce the effect of BACE1 while not effecting cell viability. CONCLUSION: The identified peptide exhibited strong binding to BACE1 in vitro and was able to reduce production of Aß, suggesting a favourable BACE1 inhibitor for future refining and characterisation.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Peptídeos/farmacologia , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Linhagem Celular , Descoberta de Drogas , Inibidores Enzimáticos/metabolismo , Humanos , Fragmentos de Peptídeos/metabolismo , Peptídeos/metabolismo
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