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1.
Postgrad Med ; 131(7): 501-508, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31483196

RESUMO

Objectives: Aiginition Longitudinal Biomarker Investigation Of Neurodegeneration (ALBION) is a longitudinal ongoing study initiated in 2018 that takes place in the Cognitive Disorders Clinic of Aiginition Hospital of the National and Kapodistrian University of Athens. Its aim is to address several research questions concerning the preclinical and prodromal stage of Alzheimer's disease and explore potential markers for early detection, prediction, and primary prevention of dementia. Methods: We here present the design and the preliminary baseline characteristics of ALBION. The sample of our study consists of people aged over 50 who are concerned about their memory but are cognitively normal (CN) or have mild cognitive deficits. Each participant undergoes an extensive assessment including several demographic, medical, social, environmental, clinical, nutritional, neuropsychological determinants and lifestyle activities. Furthermore, we are collecting data from portable devices, neuroimaging techniques and biological samples (blood, stools, CSF). All participants are assessed annually for a period of 10 years. Results: In total, 47 participants have completed the initial evaluation up to date and are divided in two groups, CN individuals (N = 26) and MCI patients (N = 21), based on their cognitive status. The participants are, on average, 64 years old, 46.3% of the sample is male with an average of 12.73 years of education. MCI patients report more comorbidities and have a lower score in the MMSE test. Regarding APOE status, 2 participants are ε4 homozygotes and 10 ε4 heterozygotes. CSF analyses (Aß42, Τ-tau, P-tau) revealed no differences between the two groups. Conclusion: The ALBION study offers an opportunity to explore preclinical dementia and identify new and tailored markers, particularly relating to lifestyle. Further investigation of these populations may provide a wider profile of the changes taking place in the preclinical phase of dementia, leading to potentially effective therapeutic and preventive strategies.


Assuntos
Doença de Alzheimer/prevenção & controle , Disfunção Cognitiva/metabolismo , Prevenção Primária , Sintomas Prodrômicos , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteínas E/genética , Biomarcadores , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/fisiopatologia , Diagnóstico Precoce , Eletroencefalografia , Feminino , Neuroimagem Funcional , Grécia , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Dados Preliminares , Proteínas tau/líquido cefalorraquidiano
2.
J Enzyme Inhib Med Chem ; 34(1): 1489-1497, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31416364

RESUMO

MAO-B leads to an increase in the levels of hydrogen peroxide and oxidative free radicals, which contribute to the aetiology of the AD. Thus, both iron ion chelators and MAO-B inhibitors can be used to treat AD. Taking the coumarin derivatives and hydroxypyridinones as the lead compounds, a series of dual-target hybrids were designed and synthesised by Click Chemistry. The compounds were biologically evaluated for their iron ion chelating and MAO-B inhibitory activity. Most of the compounds displayed excellent iron ion chelating activity and moderate to good anti-MAO-B activity. Compounds 27b and 27j exhibited the most potent MAO-B inhibitory activity, with IC50 values of 0.68 and 0.86 µM, respectively. In summary, these dual-target compounds have the potential anti-AD activity.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Cumarínicos/farmacologia , Quelantes de Ferro/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Piridonas/farmacologia , Doença de Alzheimer/metabolismo , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Humanos , Quelantes de Ferro/síntese química , Quelantes de Ferro/química , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Piridonas/síntese química , Piridonas/química , Relação Estrutura-Atividade
3.
Life Sci ; 234: 116739, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31400352

RESUMO

AIM: This study aimed to investigate the effect of icariin (referred as ICA) on Alzheimer's disease (AD) model through endoplasmic reticulum (ER) stress pathway. MAIN METHODS: Nine months male APP/PS1 and wild-type (WT) mice were randomly divided into four groups: APP/PS1 control, APP/PS1 + ICA, WT control and WT + ICA groups. The treated mice were given ICA 60 mg/kg/d and control mice were received the same volume distilled water for consecutive 3 months. The Morris water maze and Novel object recognition were used to detect animals' behavior. Nissl staining was used to observe the neuronal morphology in hippocampus area. Aß deposition in hippocampal region was observed by immunofluorescence staining. TUNEL staining was used to observe apoptosis. Detection of expression of ER stress related factors by Western blot and real time RT-PCR. KEY FINDINGS: Chronically administrated with ICA compared with APP/PS1 control mice significantly improved the behavior performance, reduced neuronal apoptosis, as well as suppressing the ER stress signaling pathway, including that decreased the level of glucose-regulated protein 78, phosphorylated ER-regulated kinase and phosphorylated eukaryotic initiation factor α, as well activating transcription factor-4, C/EBP homologous protein, DNA damage inducible protein 34 and tribbles homologous protein 3. SIGNIFICANCE: Our data indicated that ICA suppressed the ER stress signaling to protect against AD animal model, these findings suggest that a potential point for researching the effect of ICA on neurodegeneration.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Precursor de Proteína beta-Amiloide/metabolismo , Cognição/efeitos dos fármacos , Medicamentos de Ervas Chinesas/uso terapêutico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Flavonoides/uso terapêutico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Medicamentos de Ervas Chinesas/farmacologia , Flavonoides/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Memória/efeitos dos fármacos , Camundongos
4.
Chem Commun (Camb) ; 55(67): 9955-9958, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31364619

RESUMO

A silver nanocluster-based ratiometric fluorescent nanosensor was developed for the determination of ATP in the cerebrospinal fluid of a mouse brain. Using this useful tool with good stability and high selectivity as well as a wide linear detection range, it was found that the ATP concentration in a mouse brain with Alzheimer's disease was 2300-fold higher than that in a normal one.


Assuntos
Trifosfato de Adenosina/líquido cefalorraquidiano , Química Encefálica , DNA/química , Corantes Fluorescentes/química , Nanopartículas Metálicas/química , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/citologia , Encéfalo/patologia , Córtex Cerebral/química , Hipocampo/química , Camundongos , Conformação de Ácido Nucleico , Prata/química , Espectrometria de Fluorescência/métodos
5.
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
6.
Postgrad Med ; 131(7): 415-422, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31424301

RESUMO

Alzheimer's disease (AD) is the most common form of dementia manifesting as alterations in cognitive abilities, behavior, and deterioration in memory which is progressive, leading to gradual worsening of symptoms. Major pathological features of AD are accumulations of neuronal amyloid plaques and neurofibrillary tangles, with early lesions appearing primarily in the hippocampus, the area of the brain involved in memory and learning. Cardiovascular-related risk factors are believed to play a crucial role in disease development and the acceleration of cognitive deterioration by worsening cerebral perfusion, promoting disturbances in amyloid clearance. Current evidence supports hypertension, hypotension, heart failure, stroke and coronary artery diseases as potential factors playing a role in cognitive decline in patients with Alzheimer's dementia. Although dementia due to cardiovascular deficits is more strongly linked to the development of vascular dementia, a stepwise decline in cognition, recent researches have also discovered its deleterious influence on AD development.


Assuntos
Doença de Alzheimer/fisiopatologia , Doenças Cardiovasculares/fisiopatologia , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Doenças Cardiovasculares/epidemiologia , Circulação Cerebrovascular , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/fisiopatologia , Progressão da Doença , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Hipotensão/epidemiologia , Hipotensão/fisiopatologia , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/fisiopatologia
7.
BMC Bioinformatics ; 20(1): 386, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291905

RESUMO

BACKGROUND: Mathematical models of biological networks can provide important predictions and insights into complex disease. Constraint-based models of cellular metabolism and probabilistic models of gene regulatory networks are two distinct areas that have progressed rapidly in parallel over the past decade. In principle, gene regulatory networks and metabolic networks underly the same complex phenotypes and diseases. However, systematic integration of these two model systems remains a fundamental challenge. RESULTS: In this work, we address this challenge by fusing probabilistic models of gene regulatory networks into constraint-based models of metabolism. The novel approach utilizes probabilistic reasoning in BN models of regulatory networks serves as the "glue" that enables a natural interface between the two systems. Probabilistic reasoning is used to predict and quantify system-wide effects of perturbation to the regulatory network in the form of constraints for flux variability analysis. In this setting, both regulatory and metabolic networks inherently account for uncertainty. Applications leverage constraint-based metabolic models of brain metabolism and gene regulatory networks parameterized by gene expression data from the hippocampus to investigate the role of the HIF-1 pathway in Alzheimer's disease. Integrated models support HIF-1A as effective target to reduce the effects of hypoxia in Alzheimer's disease. However, HIF-1A activation is far less effective in shifting metabolism when compared to brain metabolism in healthy controls. CONCLUSIONS: The direct integration of probabilistic regulatory networks into constraint-based models of metabolism provides novel insights into how perturbations in the regulatory network may influence metabolic states. Predictive modeling of enzymatic activity can be facilitated using probabilistic reasoning, thereby extending the predictive capacity of the network. This framework for model integration is generalizable to other systems.


Assuntos
Doença de Alzheimer/metabolismo , Redes e Vias Metabólicas , Modelos Biológicos , Modelos Estatísticos , Teorema de Bayes , Enzimas/metabolismo , Redes Reguladoras de Genes , Humanos , Fenótipo , Transdução de Sinais
8.
Nat Commun ; 10(1): 2909, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266957

RESUMO

Cells form and use biomolecular condensates to execute biochemical reactions. The molecular properties of non-membrane-bound condensates are directly connected to the amino acid content of disordered protein regions. Lysine plays an important role in cellular function, but little is known about its role in biomolecular condensation. Here we show that protein disorder is abundant in protein/RNA granules and lysine is enriched in disordered regions of proteins in P-bodies compared to the entire human disordered proteome. Lysine-rich polypeptides phase separate into lysine/RNA-coacervates that are more dynamic and differ at the molecular level from arginine/RNA-coacervates. Consistent with the ability of lysine to drive phase separation, lysine-rich variants of the Alzheimer's disease-linked protein tau undergo coacervation with RNA in vitro and bind to stress granules in cells. Acetylation of lysine reverses liquid-liquid phase separation and reduces colocalization of tau with stress granules. Our study establishes lysine as an important regulator of cellular condensation.


Assuntos
Lisina/metabolismo , RNA/química , RNA/metabolismo , Proteínas tau/química , Proteínas tau/metabolismo , Acetilação , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Linhagem Celular , Grânulos Citoplasmáticos/genética , Grânulos Citoplasmáticos/metabolismo , Humanos , Lisina/química , Lisina/genética , RNA/genética , Proteínas tau/genética
9.
Phytochemistry ; 165: 112055, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31261031

RESUMO

Twenty-one known Amaryllidaceae alkaloids of various structural types and one undescribed alkaloid, named narcimatuline, have been isolated from fresh bulbs of Narcissus pseudonarcissus L. cv. Dutch Master. The chemical structures were elucidated by combination of MS, HRMS, 1D and 2D NMR spectroscopic techniques, and by comparison with literature data. Narcimatuline amalgamates two basic scaffolds of Amaryllidaceae alkaloids in its core, namely galanthamine and galanthindole. All isolated compounds were evaluated for their in vitro acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), prolyl oligopeptidase (POP), and glycogen synthase kinase-3ß (GSK-3ß) inhibitory activities. The most interesting biological profile was demonstrated by newly isolated alkaloid narcimatuline.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Alcaloides de Amaryllidaceae/farmacologia , Inibidores da Colinesterase/farmacologia , Narcissus/química , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/isolamento & purificação , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Relação Dose-Resposta a Droga , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Serina Endopeptidases/metabolismo , Relação Estrutura-Atividade
10.
Chem Pharm Bull (Tokyo) ; 67(10): 1030-1041, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31341111

RESUMO

Alzheimer's Disease (AD) is one of the most challenging diseases faced by humankind. AD is still not classified as curable because of the complex structure of pathologies underlying it. As the mean life expectancy of the world population constantly increases, the prevalence of AD and treatment costs for AD also grow rapidly. Current state of the art for AD treatment mainly consists of palliative therapy aimed at providing symptomatic relief and improving the standard of living in patients with AD. However, different research groups are working on more effective and safe drug delivery options aimed at both symptomatic relief and treatment of the underlying mechanisms. In this review, the current prevalence of AD, health costs, pathologies, and available treatment options including the ones in the market and/or under trial have been reviewed. Data in the existing literature have been presented, and future opportunities have been discussed. It is our belief that these nanotechnological products provide the required efficacy and safety profiles to enable these formulations go through phase studies and enter the market after regulatory authority approval, as with cancer. Last, but not the least the metabolomic studies will be providing useful informative data on the early diagnosis of AD, thus may be clinical implications might be delayed with the administration of therapeutic agents at the initial state of the disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Pesquisa Biomédica , Sistemas de Liberação de Medicamentos , Humanos , Nanotecnologia
11.
Nat Neurosci ; 22(7): 1099-1109, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31235907

RESUMO

Parkinson's disease, the most common age-related movement disorder, is a progressive neurodegenerative disease with unclear etiology. Key neuropathological hallmarks are Lewy bodies and Lewy neurites: neuronal inclusions immunopositive for the protein α-synuclein. In-depth ultrastructural analysis of Lewy pathology is crucial to understanding pathogenesis of this disease. Using correlative light and electron microscopy and tomography on postmortem human brain tissue from Parkinson's disease brain donors, we identified α-synuclein immunopositive Lewy pathology and show a crowded environment of membranes therein, including vesicular structures and dysmorphic organelles. Filaments interspersed between the membranes and organelles were identifiable in many but not all α-synuclein inclusions. Crowding of organellar components was confirmed by stimulated emission depletion (STED)-based super-resolution microscopy, and high lipid content within α-synuclein immunopositive inclusions was corroborated by confocal imaging, Fourier-transform coherent anti-Stokes Raman scattering infrared imaging and lipidomics. Applying such correlative high-resolution imaging and biophysical approaches, we discovered an aggregated protein-lipid compartmentalization not previously described in the Parkinsons' disease brain.


Assuntos
Membranas Intracelulares/ultraestrutura , Corpos de Lewy/ultraestrutura , Doença por Corpos de Lewy/patologia , Lipídeos de Membrana/análise , Organelas/ultraestrutura , Doença de Parkinson/patologia , alfa-Sinucleína/análise , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Hipocampo/química , Hipocampo/ultraestrutura , Humanos , Imagem Tridimensional , Corpos de Lewy/química , Doença por Corpos de Lewy/metabolismo , Mesencéfalo/química , Mesencéfalo/ultraestrutura , Microscopia Confocal , Microscopia Eletrônica/métodos , Microscopia de Fluorescência , Doença de Parkinson/metabolismo , Substância Negra/química , Substância Negra/ultraestrutura , Sequenciamento Completo do Exoma
12.
Eur J Med Chem ; 178: 726-739, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31229875

RESUMO

To discover multifunctional agents for the treatment of Alzheimer's disease (AD), a series of chalcone-O-carbamate derivatives was designed and synthesized based on the multitarget-directed ligands strategy. The in vitro biological activities were evaluated including AChE/BChE inhibition, MAO-A/MAO-B inhibition, antioxidant activities, Aß1-42 aggregation inhibition, metal-chelating properties and neuroprotective effects against H2O2-induced PC12 cell injury. The results showed compounds 5b and 5h indicated highly selective BChE inhibitory activity with IC50 values of 3.1 µM and 1.2 µM, respectively and showed highly selective MAO-B inhibitory potency with IC50 values of 1.3 µM and 3.7 µM, respectively. In addition, compounds 5b and 5h could inhibit self-induced Aß1-42 aggregation with 63.9% and 53.1% inhibition percent rate, respectively. Particularly, compound 5b was a potent antioxidant agent and neuroprotectant, as well as a selective metal chelator by chelating Cu2+ and Al3+. Moreover, compound 5b could inhibit and disaggregate Cu2+-induced Aß1-42 aggregation, which was further supported by the TEM images. Furthermore, compounds 5b and 5h could cross the blood-brain barrier (BBB) in vitro and conformed to the Lipinski's rule of five. Finally, the in vivo assay exhibited that compound 5b could improve scopolamine-induced cognitive impairment. Taken together, these results revealed that compound 5b might be a potential multifunctional agent for the treatment of AD, and deserved to do further structure optimization.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Chalconas/farmacologia , Inibidores da Colinesterase/farmacologia , Desenho de Drogas , Inibidores da Monoaminoxidase/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Butirilcolinesterase/metabolismo , Chalconas/síntese química , Chalconas/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Enguias , Feminino , Cavalos , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Modelos Moleculares , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Fragmentos de Peptídeos/antagonistas & inibidores , Agregados Proteicos/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade
13.
Cell Mol Life Sci ; 76(16): 3167-3191, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31197405

RESUMO

As life expectancy increases worldwide, age-related neurodegenerative diseases will increase in parallel. The lack of effective treatment strategies may soon lead to an unprecedented health, social and economic crisis. Any attempt to halt the progression of these diseases requires a thorough knowledge of the pathophysiological mechanisms involved to facilitate the identification of new targets and the application of innovative therapeutic strategies. The metzincin superfamily of metalloproteinases includes matrix metalloproteinases (MMP), a disintegrin and metalloproteinase (ADAM) and ADAM with thrombospondin motifs (ADAMTS). These multigenic and multifunctional proteinase families regulate the functions of an increasing number of signalling and scaffolding molecules involved in neuroinflammation, blood-brain barrier disruption, protein misfolding, synaptic dysfunction or neuronal death. Metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), are therefore, at the crossroads of molecular and cellular mechanisms that support neurodegenerative processes, and emerge as potential new therapeutic targets. We provide an overview of current knowledge on the role and regulation of metalloproteinases and TIMPs in four major neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease.


Assuntos
Doença de Alzheimer/patologia , Metaloproteinases da Matriz/metabolismo , Doenças Neurodegenerativas/patologia , Inibidores Teciduais de Metaloproteinases/metabolismo , Proteínas ADAM/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Humanos , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Doenças Neurodegenerativas/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia
14.
Cell Mol Life Sci ; 76(16): 3193-3206, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31201463

RESUMO

Alzheimer's Disease (AD) is the sixth-leading cause of death in industrialized countries. Neurotoxic amyloid-ß (Aß) plaques are one of the pathological hallmarks in AD patient brains. Aß accumulates in the brain upon sequential, proteolytic processing of the amyloid precursor protein (APP) by ß- and γ-secretases. However, so far disease-modifying drugs targeting ß- and γ-secretase pathways seeking a decrease in the production of toxic Aß peptides have failed in clinics. It has been demonstrated that the metalloproteinase meprin ß acts as an alternative ß-secretase, capable of generating truncated Aß2-x peptides that have been described to be increased in AD patients. This indicates an important ß-site cleaving enzyme 1 (BACE-1)-independent contribution of the metalloprotease meprin ß within the amyloidogenic pathway and may lead to novel drug targeting avenues. However, meprin ß itself is embedded in a complex regulatory network. Remarkably, the anti-amyloidogenic α-secretase a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) is a direct competitor for APP at the cell surface, but also a sheddase of inactive pro-meprin ß. Overall, we highlight the current cellular, molecular and structural understanding of meprin ß as alternative ß-secretase within the complex protease web, regulating APP processing in health and disease.


Assuntos
Proteína ADAM10/metabolismo , Metaloendopeptidases/metabolismo , Proteína ADAM10/química , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Metaloendopeptidases/química , Presenilina-1/metabolismo , Proteólise , Serina Endopeptidases/metabolismo
15.
BMC Genomics ; 20(Suppl 6): 434, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31189471

RESUMO

BACKGROUND: Biological networks describes the mechanisms which govern cellular functions. Temporal networks show how these networks evolve over time. Studying the temporal progression of network topologies is of utmost importance since it uncovers how a network evolves and how it resists to external stimuli and internal variations. Two temporal networks have co-evolving subnetworks if the evolving topologies of these subnetworks remain similar to each other as the network topology evolves over a period of time. In this paper, we consider the problem of identifying co-evolving subnetworks given a pair of temporal networks, which aim to capture the evolution of molecules and their interactions over time. Although this problem shares some characteristics of the well-known network alignment problems, it differs from existing network alignment formulations as it seeks a mapping of the two network topologies that is invariant to temporal evolution of the given networks. This is a computationally challenging problem as it requires capturing not only similar topologies between two networks but also their similar evolution patterns. RESULTS: We present an efficient algorithm, Tempo, for solving identifying co-evolving subnetworks with two given temporal networks. We formally prove the correctness of our method. We experimentally demonstrate that Tempo scales efficiently with the size of network as well as the number of time points, and generates statistically significant alignments-even when evolution rates of given networks are high. Our results on a human aging dataset demonstrate that Tempo identifies novel genes contributing to the progression of Alzheimer's, Huntington's and Type II diabetes, while existing methods fail to do so. CONCLUSIONS: Studying temporal networks in general and human aging specifically using Tempo enables us to identify age related genes from non age related genes successfully. More importantly, Tempo takes the network alignment problem one huge step forward by moving beyond the classical static network models.


Assuntos
Algoritmos , Evolução Molecular , Redes Reguladoras de Genes , Redes e Vias Metabólicas , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Biologia Computacional/métodos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Doença de Huntington/genética , Doença de Huntington/metabolismo , Pessoa de Meia-Idade , Mapeamento de Interação de Proteínas , Adulto Jovem
16.
Chem Biodivers ; 16(7): e1900144, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31155827

RESUMO

A new series of coumarin-3-carboxamide-N-morpholine hybrids 5a-5l was designed and synthesized as cholinesterases inhibitors. The synthetic approach for title compounds was started from the reaction between 2-hydroxybenzaldehyde derivatives and Meldrum's acid to afford corresponding coumarin-3-carboxylic acids. Then, amidation of the latter compounds with 2-morpholinoethylamine or N-(3-aminopropyl)morpholine led to the formation of the compounds 5a-5l. The in vitro inhibition screen against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) revealed that most of the synthesized compounds had potent AChE inhibitory while their BuChE inhibitions are moderate to weak. Among them, propylmorpholine derivative 5g (N-[3-(morpholin-4-yl)propyl]-2-oxo-2H-chromene-3-carboxamide) bearing an unsubstituted coumarin moiety and ethylmorpholine derivative 5d (6-bromo-N-[2-(morpholin-4-yl)ethyl]-2-oxo-2H-chromene-3-carboxamide) bearing a 6-bromocoumarin moiety showed the most activity against AChE and BuChE, respectively. The inhibitory activity of compound 5g against AChE was 1.78 times more than that of rivastigmine and anti-BuChE activity of compound 5d is approximately same as rivastigmine. Kinetic and docking studies confirmed the dual binding site ability of compound 5g to inhibit AChE.


Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Desenho de Drogas , Morfolinas/farmacologia , Doença de Alzheimer/metabolismo , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Electrophorus , Cavalos , Cinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Morfolinas/síntese química , Morfolinas/química
17.
Chem Biol Interact ; 309: 108707, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31194956

RESUMO

Alzheimer's disease (AD) is a slow but progressive neurodegenerative disease. One of the pathological hallmarks of AD is the progressive accumulation of ß-amyloid (Aß) in the form of senile plaques, and Aß insult to neuronal cells has been identified as one of the major causes of AD onset. In the present study, we investigated the anti-AD potential of four flavonoids, naringenin, didymin, prunin, and poncirin, by evaluating their ability to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and ß-site amyloid precursor protein cleaving enzyme 1 (BACE1). All four flavonoids displayed promising inhibitory activity against AChE, BChE, and BACE1. Structure-activity relationships suggested that glycosylation of naringenin at sugar moieties, and at different positions of the glycosidic linkage, might be closely associated with anti-AD potential. Kinetic and docking studies showed the lowest binding energy and highest affinity for the mixed, competitive, and non-competitive type inhibitors didymin, prunin, and poncirin. Hydrophobic interactions and the number of hydrogen bonds determined the strength of the protein-inhibitor interaction. We also examined the neuroprotective mechanisms by which flavonoids act against Aß25-35-induced toxicity in PC12 cells. Exposure of PC12 cells to 10 µM Aß25-35 for 24 h resulted in a significant decrease in cell viability. In addition, pretreatment of PC12 cells with different concentrations of flavonoids for 1 h significantly reversed the effects of Aß. Furthermore, treatment with the most active flavonoid, didymin, significantly reduced BACE1, APPsß, and C99 expression levels in a dose-dependent manner, without affecting amyloid precursor protein (APP) levels in the amyloidogenic pathway. Together, our results indicate that flavonoids, and in particular didymin, exhibit inhibitory activity in vitro, and may be useful in the development of therapeutic modalities for the treatment of AD.


Assuntos
Acetilcolinesterase/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Butirilcolinesterase/metabolismo , Flavanonas/química , Glicosídeos/farmacologia , Agregados Proteicos/efeitos dos fármacos , Acetilcolinesterase/química , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/farmacologia , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Sítios de Ligação , Butirilcolinesterase/química , Domínio Catalítico , Sobrevivência Celular/efeitos dos fármacos , Glicosídeos/química , Cinética , Simulação de Acoplamento Molecular , Células PC12 , Fragmentos de Peptídeos/farmacologia , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Ratos , Relação Estrutura-Atividade
18.
Curr Top Med Chem ; 19(13): 1173-1187, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31244427

RESUMO

BACKGROUND: Alzheimers Disease (AD) is a neurodegenerative disease which is characterized by the deposition of amyloid plaques in the brain- a concept supported by most of the researchers worldwide. The main component of the plaques being amyloid-beta (Aß42) results from the sequential cleavage of Amyloid precursor protein (APP) by beta and gamma secretase. This present study intends to inhibit the formation of amyloid plaques by blocking the action of gamma secretase protein with Inhibitors (GSI). METHODS: A number of Gamma Secretase Inhibitors (GSI) were targeted to the protein by molecular docking. The inhibitor having the best affinity was used as a subject for further virtual screening methods to obtain similar compounds. The generated compounds were docked again at the same docking site on the protein to find a compound with higher affinity to inhibit the protein. The highlights of virtually screened compound consisted of Pharmacophore Mapping of the docking site. These steps were followed by comparative assessments for both the compounds, obtained from the two aforesaid docking studies, which included interaction energy descriptors, ADMET profiling and PreADMET evaluations. RESULTS: 111 GSI classified as azepines, sulfonamides and peptide isosteres were used in the study. By molecular docking an amorpholino-amide, compound (22), was identified to be the high affinity compound GSI along with its better interaction profiles.The virtually screened pubchem compound AKOS001083915 (CID:24462213) shows the best affinity with gamma secretase. Collective Pharmacophore mapping (H bonds, electrostatic profile, binding pattern and solvent accesibility) shows a stable interaction. The resulting ADMETand Descriptor values were nearly equivalent. CONCLUSION: These compounds identified herein hold a potential as Gamma Secretase inhibitors.According to PreADMET values the compound AKOS001083915 is effective and specific to the target protein. Its BOILED-egg plot analysis infers the compound permeable to blood brain barrier.Comparative study for both the compounds resulted in having nearly equivalent properties. These compounds have the capacity to inhibit the protein which is indirectly responsible for the formation of amyloid plaques and can be further put to in vitro pharmacokinetic and dynamic studies.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Amidas/farmacologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Morfolinas/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Doença de Alzheimer/metabolismo , Amidas/síntese química , Amidas/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligações de Hidrogênio , Simulação de Acoplamento Molecular , Morfolinas/síntese química , Morfolinas/química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
19.
J Agric Food Chem ; 67(27): 7684-7693, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31203623

RESUMO

This study investigated the alleviative effect of caffeic acid (CA) on Alzheimer's disease (AD) pathogenesis and associated mechanisms in high-fat (HF) diet-induced hyperinsulinemic rats. The results of a Morris water maze indicated that, by administrating CA (30 mg/kg b.w./day) for 30 weeks, the memory and learning impairments in HF-induced hyperinsulinemic rats were significantly ameliorated. CA also enhanced superoxide dismutase and glutathione free radical scavenger activity in hyperinsulinemic rats. The Western blot data further confirmed that protein expressions of phosphorylated-glycogen synthase kinase 3ß (GSK3ß) were significantly increased, whereas the expression of phosphorylated-tau protein decreased in the hippocampus of rats administered with CA in comparison with the HF group. Moreover, the expression of amyloid precursor protein (APP) and ß-site APP cleaving enzyme were attenuated, subsequently lowering the level of ß-amyloid 1-42 (Aß 1-42) in the hippocampus of CA-treated hyperinsulinemic rats. CA also significantly increased the expression of synaptic proteins in HF rats.


Assuntos
Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Ácidos Cafeicos/administração & dosagem , Insulina/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Animais , Antioxidantes/química , Córtex Cerebral/química , Córtex Cerebral/enzimologia , Córtex Cerebral/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Glutationa/metabolismo , Glicogênio Sintase Quinase 3 beta/análise , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/química , Hipocampo/enzimologia , Hipocampo/metabolismo , Hiperinsulinismo/etiologia , Hiperinsulinismo/metabolismo , Masculino , Fosforilação , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Proteínas tau/análise , Proteínas tau/metabolismo
20.
Nat Commun ; 10(1): 2353, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164641

RESUMO

The link between brain amyloid-ß (Aß), metabolism, and dementia symptoms remains a pressing question in Alzheimer's disease. Here, using positron emission tomography ([18F]florbetapir tracer for Aß and [18F]FDG tracer for glucose metabolism) with a novel analytical framework, we found that Aß aggregation within the brain's default mode network leads to regional hypometabolism in distant but functionally connected brain regions. Moreover, we found that an interaction between this hypometabolism with overlapping Aß aggregation is associated with subsequent cognitive decline. These results were also observed in transgenic Aß rats that do not form neurofibrillary tangles, which support these findings as an independent mechanism of cognitive deterioration. These results suggest a model in which distant Aß induces regional metabolic vulnerability, whereas the interaction between local Aß with a vulnerable environment drives the clinical progression of dementia.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Emaranhados Neurofibrilares/metabolismo , Doença de Alzheimer/diagnóstico por imagem , Compostos de Anilina , Animais , Animais Geneticamente Modificados , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Etilenoglicóis , Fluordesoxiglucose F18 , Humanos , Imagem por Ressonância Magnética , Vias Neurais/diagnóstico por imagem , Vias Neurais/metabolismo , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Ratos
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