RESUMEN
Glycogen synthase kinase-3 (GSK3), consisting of GSK3α and GSK3ß subtypes, is a complex protein kinase that regulates numerous substrates. Research has observed increased GSK3 expression in the brains of Alzheimer's disease (AD) patients and models. AD is a neurodegenerative disorder with diverse pathogenesis and notable cognitive impairments, characterized by Aß aggregation and excessive tau phosphorylation. This article provides an overview of GSK3's structure and regulation, extensively analyzing its relationship with AD factors. GSK3 overactivation disrupts neural growth, development, and function. It directly promotes tau phosphorylation, regulates amyloid precursor protein (APP) cleavage, leading to Aß formation, and directly or indirectly triggers neuroinflammation and oxidative damage. We also summarize preclinical research highlighting the inhibition of GSK3 activity as a primary therapeutic approach for AD. Finally, pending issues like the lack of highly specific and affinity-driven GSK3 inhibitors, are raised and expected to be addressed in future research. In conclusion, GSK3 represents a target in AD treatment, filled with hope, challenges, opportunities, and obstacles.
Asunto(s)
Enfermedad de Alzheimer , Glucógeno Sintasa Quinasa 3 , Animales , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/enzimología , Precursor de Proteína beta-Amiloide/metabolismo , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/metabolismo , Proteínas tau/metabolismo , Proteínas tau/antagonistas & inhibidoresRESUMEN
Targeting dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) has been verified to regulate the progression of tau pathology as a promising treatment for Alzheimer's disease (AD), while the research progress on DYRK1A inhibitors seemed to be in a bottleneck period. In this work, we identified 32 (ZJCK-6-46) as the most potential DYRK1A inhibitor (IC50 = 0.68 nM) through rational design, systematic structural optimization, and comprehensive evaluation. Compound 32 exhibited acceptable in vitro absorption, distribution, metabolism, and excretion (ADME) properties and significantly reduced the expression of p-Tau Thr212 in Tau (P301L) 293T cells and SH-SY5Y cells. Moreover, compound 32 showed favorable bioavailability, blood-brain barrier (BBB) permeability, and the potential of ameliorating cognitive dysfunction by obviously reducing the expression of phosphorylated tau and neuronal loss in vivo, which was deserved as a valuable molecular tool to reveal the role of DYRK1A in the pathogenesis of AD and to further promote the development of anti-AD drugs.
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Enfermedad de Alzheimer , Quinasas DyrK , Inhibidores de Proteínas Quinasas , Proteínas Serina-Treonina Quinasas , Proteínas Tirosina Quinasas , Proteínas tau , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Humanos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas tau/metabolismo , Proteínas tau/antagonistas & inhibidores , Relación Estructura-Actividad , Administración Oral , Masculino , Ratas , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Células HEK293 , Ratones , Descubrimiento de Drogas , Fosforilación/efectos de los fármacos , Simulación del Acoplamiento Molecular , Ratas Sprague-DawleyRESUMEN
Amyloid-ß (Aß) plaques and neurofibrillary tangles containing phosphorylated tau protein are major hallmarks of Alzheimer's disease (AD). Drug discovery efforts to target Aß and tau have been the primary focus for several decades. Recently, substantial breakthroughs have been achieved in the clinical development of Aß antibodies; aducanumab was approved under conditional accelerated pathway by Food and Drug Administration (FDA) in the U.S. as the first disease-modifying agent for treating AD, and lecanemab has been granted traditional full approved in the U.S. and Japan. In addition, donanemab met the primary endpoint in a phase 3 study. On the other hand, tau-targeting therapies have failed to show clinical benefit although that increased tau levels show a strong correlation with cognitive impairment relative to Aß depositions. Currently, tau immunotherapies, such as anti-tau antibodies and tau vaccines, have shown functional benefits in clinical trials. Also, clinical trials for combination therapy of Aß and tau antibodies to see their potential are being investigated. In this review, we provide updates on the results of clinical trials of anti-Aß antibodies and anti-tau therapeutics and suggest future directions for these therapeutics.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Proteínas tau , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/inmunología , Humanos , Proteínas tau/antagonistas & inhibidores , Proteínas tau/metabolismo , Proteínas tau/inmunología , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/inmunología , Inmunoterapia , AnimalesRESUMEN
Alzheimer's disease (AD) is the most common form of senile dementia, presenting a significant challenge for the development of effective treatments. AD is characterized by extracellular amyloid plaques and intraneuronal neurofibrillary tangles. Therefore, targeting both hallmarks through inhibition of amyloid beta (Aß) and tau aggregation presents a promising approach for drug development. Carbon dots (CD), with their high biocompatibility, minimal cytotoxicity, and blood-brain barrier (BBB) permeability, have emerged as promising drug nanocarriers. Congo red, an azo dye, has gathered significant attention for inhibiting amyloid-beta and tau aggregation. However, Congo red's inability to cross the BBB limits its potential to be used as a drug candidate for central nervous system (CNS) diseases. Furthermore, current studies only focus on using Congo red to target single disease hallmarks, without investigating dual inhibition capabilities. In this study, we synthesized Congo red-derived CD (CRCD) by using Congo red and citric acid as precursors, resulting in three variants, CRCD1, CRCD2 and CRCD3, based on different mass ratios of precursors. CRCD2 and CRCD3 exhibited sustained low cytotoxicity, and CRCD3 demonstrated the ability to traverse the BBB in a zebrafish model. Moreover, thioflavin T (ThT) aggregation assays and AFM imaging revealed CRCD as potent inhibitors against both tau and Aß aggregation. Notably, CRCD1 emerged as the most robust inhibitor, displaying IC50 values of 0.2 ± 0.1 and 2.1 ± 0.5 µg/mL against tau and Aß aggregation, respectively. Our findings underscore the dual inhibitory role of CRCD against tau and Aß aggregation, showcasing effective BBB penetration and positioning CRCD as potential nanodrugs and nanocarriers for the CNS. Hence, CRCD-based compounds represent a promising candidate in the realm of multi-functional AD therapeutics, offering an innovative formulation component for future developments in this area. STATEMENT OF SIGNIFICANCE: This article reports Congo red-derived carbon dots (CRCD) as dual inhibitors of tau and amyloid-beta (Aß) aggregation for the treatment of Alzheimer's disease (AD). The CRCD are biocompatible and show strong fluorescence, high stability, the ability to cross the blood-brain barrier, and the function of addressing two major pathological features of AD.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Carbono , Pez Cebra , Proteínas tau , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Carbono/química , Proteínas tau/metabolismo , Proteínas tau/antagonistas & inhibidores , Humanos , Rojo Congo/química , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Agregado de Proteínas/efectos de los fármacos , Puntos Cuánticos/químicaRESUMEN
Alzheimer's disease (AD) and other taupathies are neurodegenerative disorders associated with the amyloid deposition of the Tau protein in the brain. This amyloid formation may be inhibited by small molecules, which is recognized as one of the best therapeutic strategies to stop the progression of the disease. This work focuses on the small nucleating segment, hexapeptide-paired helical filament 6 (PHF6), responsible for Tau aggregation. Using computational modeling and classical molecular dynamics simulations, we show that PHF6 monomers collapse in water to form ß-sheet rich structures, and the main olive oil polyphenol oleuropein aglycone (OleA) prevents peptide aggregation significantly. We gradually increase the ratio of the PHF6-OleA from 1:1 to 1:3 and find that for the 1:1 ratio, the peptide monomers are prone to form aggregated structures, while for the 1:2 ratio, the formation of the extended ß-sheet structure is significantly less. For a 1:3 ratio of protein/OleA, the peptide residues are sufficiently crowded by OleA molecules through hydrogen bonding, hydrophobic interactions, and π-π stacking; hence, the peptide chains prefer to exist in a monomeric random coil conformation.
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Simulación de Dinámica Molecular , Aceite de Oliva , Proteínas tau , Aceite de Oliva/química , Proteínas tau/química , Proteínas tau/metabolismo , Proteínas tau/antagonistas & inhibidores , Oligopéptidos/química , Humanos , Glucósidos Iridoides/química , Glucósidos Iridoides/farmacología , Monoterpenos Ciclopentánicos , Acetatos , PiranosRESUMEN
The escalating prevalence of Alzheimer's disease (AD) has prompted extensive research into potential therapeutic interventions, with a specific focus on molecular targets such as amyloid beta (Aß) and tau protein aggregation. In this study, a series of α-ketoamide derivatives was synthesized from ß,γ-unsaturated α-keto thioesters, achieving high purity and good yield. Thioflavin T based Aß aggregation assay identified four promising compounds (BD19, BD23, BD24, and BD27) that demonstrated significant inhibitory effects on Aß aggregation. BD23, selected for its better solubility (0.045 ± 0.0012 mg/ml), was further subjected to in vitro Parallel Artificial Membrane Permeability Assay to determine the Blood-Brain-Barrier permeability and emerged as BBB permeable with permeability rate (Pe) of 10.66 ± 8.11 × 10-6 cm/s. In addition to its Aß inhibitory properties, BD23 exhibited significant inhibition of heparin-induced tau aggregation and demonstrated non-toxicity in SHSY5Y cell lines. Subsequent in vivo assays were conducted, administering compound BD23 to an Aß induced mouse model of AD at various doses (1, 2, & 5 mg/kg). The results revealed a noteworthy enhancement in cognitive functions, particularly when BD23 was administered at a dosage of 5 mg/kg, comparable to the effects observed with the standard dose of Donepezil (DNP). In silico investigations, including molecular docking, molecular dynamics simulations, and Density Functional Theory calculations provided insights into BD23's interactions with the targets and electronic properties. These analyses contribute to the understanding of the therapeutic potential of the lead compounds BD23 which further pave the way for further exploration of its therapeutic potential in the context of AD.
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Enfermedad de Alzheimer , Amidas , Péptidos beta-Amiloides , Relación Dosis-Respuesta a Droga , Agregado de Proteínas , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Humanos , Animales , Ratones , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Amidas/química , Amidas/farmacología , Amidas/síntesis química , Agregado de Proteínas/efectos de los fármacos , Relación Estructura-Actividad , Estructura Molecular , Simulación del Acoplamiento Molecular , Proteínas tau/metabolismo , Proteínas tau/antagonistas & inhibidores , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , MasculinoRESUMEN
Tauopathy, neuronal atrophy, and psychological impairments are hallmarks of neurodegenerative diseases, such as Alzheimer's disease, that currently lack efficacious clinical treatments capable of rectifying these issues. To address these unmet needs, we used rational drug design to combine the pharmacophores of DYRK1A inhibitors and isoDMTs to develop psychoplastogenic DYRK1A inhibitors. Using this approach, we discovered a nonhallucinogenic compound capable of promoting cortical neuron growth and suppressing tau hyperphosphorylation while also having the potential to mitigate the biological and psychological symptoms of dementia. Together, our results suggest that hybridization of the DYRK1A and psychoplastogen pharmacophores represents a promising strategy for identifying compounds that might address the cognitive as well as the behavioral and psychological symptoms of dementia.
Asunto(s)
Enfermedad de Alzheimer , Quinasas DyrK , Inhibidores de Proteínas Quinasas , Proteínas Serina-Treonina Quinasas , Proteínas Tirosina Quinasas , Proteínas tau , Enfermedad de Alzheimer/tratamiento farmacológico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Humanos , Animales , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas tau/metabolismo , Proteínas tau/antagonistas & inhibidores , Ratones , Fosforilación , Diseño de FármacosRESUMEN
Neurodegenerative diseases (NDDs) refer to a complex heterogeneous group of diseases which are associated with the accumulation of amyloid fibrils or plaques in the brain leading to progressive loss of neuronal functions. Alzheimer's disease is one of the major NDD responsible for 60-80 % of all dementia cases. Currently, there are no curative or disease-reversing/modifying molecules for many of the NDDs except a few such as donepezil, rivastigmine, galantamine, carbidopa and levodopa which treat the disease-associated symptoms. Similarly, there are very few FDA-approved tracers such as flortaucipir (Tauvid) for tau fibril imaging and florbetaben (Neuraceq), flutemetamol (Vizamyl), and florbetapir (Amyvid) for amyloid imaging available for diagnosis. Recent advances in the cryogenic electron microscopy reported distinctly different microstructures for tau fibrils associated with different tauopathies highlighting the possibility to develop tauopathy-specific imaging agents and therapeutics. In addition, it is important to identify the proteins that are associated with disease development and progression to know about their 3D structure to develop various diagnostics, therapeutics and theranostic agents. The current article discusses in detail the disease-associated amyloid and non-amyloid proteins along with their structural insights. We comprehensively discussed various novel proteins associated with NDDs and their implications in disease pathology. In addition, we document various emerging chemical compounds developed for diagnosis and therapy of different NDDs with special emphasis on theranostic agents for better management of NDDs.
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Enfermedades Neurodegenerativas , Humanos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Proteínas tau/metabolismo , Proteínas tau/antagonistas & inhibidores , Amiloide/metabolismo , Amiloide/antagonistas & inhibidores , Amiloide/química , Proteínas Amiloidogénicas/metabolismo , Proteínas Amiloidogénicas/química , Proteínas Amiloidogénicas/antagonistas & inhibidores , Nanomedicina Teranóstica , AnimalesRESUMEN
INTRODUCTION: Tauopathies are a spectrum of clinicopathological neurodegenerative disorders with increased aggregates included in glia and/or neurons of hyperphosphorylated insoluble tau protein, a microtubule-associated protein. Progressive supranuclear palsy (PSP) is an atypical dopaminergic-resistant parkinsonian syndrome, considered as a primary tauopathy with possible alteration of tau isoform ratio, and tau accumulations characterized by 4 R tau species as the main neuropathological lesions. AREAS COVERED: In the present review article, we analyzed and discussed viable disease-modifying and some symptomatic pharmacological therapeutics for PSP syndrome (PSPS). EXPERT OPINION: Pharmacological therapy for PSPS may interfere with the aggregation process or promote the clearance of abnormal tau aggregates. A variety of past and ongoing disease-modifying therapies targeting tau in PSPS included genetic, microtubule-stabilizing compounds, anti-phosphorylation, and acetylation agents, antiaggregant, protein removal, antioxidant neuronal and synaptic growth promotion therapies. New pharmacological gene-based approaches may open alternative prevention pathways for the deposition of abnormal tau in PSPS such as antisense oligonucleotide (ASO)-based drugs. Moreover, kinases and ubiquitin-proteasome systems could also be viable targets.
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Parálisis Supranuclear Progresiva , Proteínas tau , Humanos , Parálisis Supranuclear Progresiva/tratamiento farmacológico , Proteínas tau/metabolismo , Proteínas tau/antagonistas & inhibidores , Animales , Tauopatías/tratamiento farmacológico , Tauopatías/patología , Tauopatías/genética , Tauopatías/metabolismoRESUMEN
Biomarkers are the most significant diagnosis tools tending towards unique approaches and solutions for the prevention and cure of Alzheimer's Disease (AD). The current report provides a clear perception of the concept of various biomarkers and their prominent features through analysis to provide a possible solution for the inhibition of events in AD. Scientists around the world truly believe that crucial hallmarks can serve as critical tools in the early diagnosis, cure, and prevention, as well as the future of medicine. The awareness and understanding of such biomarkers would provide solutions to the puzzled mechanism of this neuronal disorder. Some of the argued biomarkers in the present article are still in an experimental phase as they need to undergo specific clinical trials before they can be considered for treatment.
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Enfermedad de Alzheimer , Biomarcadores , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/metabolismo , Humanos , Biomarcadores/análisis , Biomarcadores/metabolismo , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Proteínas tau/metabolismo , Proteínas tau/antagonistas & inhibidoresRESUMEN
Pathological hyperphosphorylation and aggregation of microtubule-associated Tau protein contribute to Alzheimer's Disease (AD) and other related tauopathies. Currently, no cure exists for Alzheimer's Disease. Aptamers offer significant potential as next-generation therapeutics in biotechnology and the treatment of neurological disorders. Traditional aptamer selection methods for Tau protein focus on binding affinity rather than interference with pathological Tau. In this study, we developed a new selection strategy to enrich DNA aptamers that bind to surviving monomeric Tau protein under conditions that would typically promote Tau aggregation. Employing this approach, we identified a set of aptamer candidates. Notably, BW1c demonstrates a high binding affinity (Kd=6.6â nM) to Tau protein and effectively inhibits arachidonic acid (AA)-induced Tau protein oligomerization and aggregation. Additionally, it inhibits GSK3ß-mediated Tau hyperphosphorylation in cell-free systems and okadaic acid-mediated Tau hyperphosphorylation in cellular milieu. Lastly, retro-orbital injection of BW1c tau aptamer shows the ability to cross the blood brain barrier and gain access to neuronal cell body. Through further refinement and development, these Tau aptamers may pave the way for a first-in-class neurotherapeutic to mitigate tauopathy-associated neurodegenerative disorders.
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Enfermedad de Alzheimer , Tauopatías , Proteínas tau , Humanos , Enfermedad de Alzheimer/metabolismo , Neuronas/metabolismo , Ácido Ocadaico/metabolismo , Ácido Ocadaico/farmacología , Ácido Ocadaico/uso terapéutico , Fosforilación , Proteínas tau/antagonistas & inhibidores , Proteínas tau/metabolismo , Tauopatías/tratamiento farmacológico , Tauopatías/metabolismo , Tauopatías/patología , Aptámeros de Nucleótidos/química , Aptámeros de Nucleótidos/farmacologíaRESUMEN
Alzheimer's disease (AD) is an onset and incurable neurodegenerative disorder that has been linked to various genetic, environmental, and lifestyle factors. Recent research has revealed several potential targets for drug development, such as the prevention of Aß production and removal, prevention of tau hyperphosphorylation, and keeping neurons alive. Drugs that target numerous ADrelated variables have been developed, and early results are encouraging. This review provides a concise map of the different receptor signaling pathways associated with Alzheimer's Disease, as well as insight into drug design based on these pathways. It discusses the molecular mechanisms of AD pathogenesis, such as oxidative stress, aging, Aß turnover, thiol groups, and mitochondrial activities, and their role in the disease. It also reviews the potential drug targets, in vivo active agents, and docking studies done in AD and provides prospects for future drug development. This review intends to provide more clarity on the molecular processes that occur in Alzheimer's patient's brains, which can be of use in diagnosing and preventing the condition.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Humanos , Animales , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Terapia Molecular Dirigida/métodos , Proteínas tau/metabolismo , Proteínas tau/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
Alzheimer's disease (AD) is characterized by a complex pathological landscape, necessitating a comprehensive treatment approach. This concise review paper delves into the idea of addressing multiple mechanisms in AD, summarizing the latest research findings on pathogenesis, risk factors, diagnostics, and therapeutic strategies. The etiology of AD is multifaceted, involving genetic, environmental, and lifestyle factors. The primary feature is the accumulation of amyloid-- beta and tau proteins, leading to neuroinflammation, synaptic dysfunction, oxidative stress, and neuronal loss. Conventional single-target therapies have shown limited effectiveness, prompting a shift toward simultaneously addressing multiple disease-related processes. Recent advancements in AD research underscore the potential of multifaceted therapies. This review explores strategies targeting both tau aggregation and amyloid-beta, along with interventions to alleviate neuroinflammation, enhance synaptic function, and reduce oxidative stress. In conclusion, the review emphasizes the growing importance of addressing various pathways in AD treatment. A holistic approach that targets different aspects of the disease holds promise for developing effective treatments and improving the quality of life for Alzheimer's patients and their caregivers.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Humanos , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Estrés Oxidativo/efectos de los fármacos , Proteínas tau/antagonistas & inhibidores , Proteínas tau/metabolismo , AnimalesRESUMEN
Advances in tau biology and the difficulties of amyloid-directed immunotherapeutics have heightened interest in tau as a target for small molecule drug discovery for neurodegenerative diseases. Here, we evaluated OLX-07010, a small molecule inhibitor of tau self-association, for the prevention of tau aggregation. The primary endpoint of the study was statistically significant reduction of insoluble tau aggregates in treated JNPL3 mice compared with Vehicle-control mice. Secondary endpoints were dose-dependent reduction of insoluble tau aggregates, reduction of phosphorylated tau, and reduction of soluble tau. This study was performed in JNPL3 mice, which are representative of inherited forms of 4-repeat tauopathies with the P301L tau mutation (e.g., progressive supranuclear palsy and frontotemporal dementia). The P301L mutation makes tau prone to aggregation; therefore, JNPL3 mice present a more challenging target than mouse models of human tau without mutations. JNPL3 mice were treated from 3 to 7 months of age with Vehicle, 30 mg/kg compound dose, or 40 mg/kg compound dose. Biochemical methods were used to evaluate self-associated tau, insoluble tau aggregates, total tau, and phosphorylated tau in the hindbrain, cortex, and hippocampus. The Vehicle group had higher levels of insoluble tau in the hindbrain than the Baseline group; treatment with 40 mg/kg compound dose prevented this increase. In the cortex, the levels of insoluble tau were similar in the Baseline and Vehicle groups, indicating that the pathological phenotype of these mice was beginning to emerge at the study endpoint and that there was a delay in the development of the phenotype of the model as originally characterized. No drug-related adverse effects were observed during the 4-month treatment period.
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Enfermedades Neurodegenerativas , Tauopatías , Proteínas tau , Animales , Humanos , Ratones , Modelos Animales de Enfermedad , Ratones Transgénicos , Rombencéfalo/metabolismo , Proteínas tau/antagonistas & inhibidores , Proteínas tau/metabolismo , Tauopatías/tratamiento farmacológico , Tauopatías/prevención & control , Tauopatías/genéticaRESUMEN
Neuronal clearance of proteins in the brain proves to be important for immunotherapy.
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Anticuerpos Monoclonales , Encéfalo , Inmunoterapia , Neuronas , Tauopatías , Proteínas tau , Encéfalo/inmunología , Encéfalo/patología , Neuronas/inmunología , Neuronas/patología , Tauopatías/terapia , Proteínas tau/antagonistas & inhibidores , Proteínas tau/inmunología , Anticuerpos Monoclonales/uso terapéutico , Humanos , Animales , RatonesAsunto(s)
Enfermedad de Alzheimer , Anticuerpos Monoclonales , Fármacos Neuroprotectores , Proteínas tau , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/inmunología , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Humanos , Fármacos Neuroprotectores/inmunología , Fármacos Neuroprotectores/uso terapéutico , Proteínas tau/antagonistas & inhibidores , Proteínas tau/inmunologíaRESUMEN
Neurodegenerative diseases are characterized by the pathologic accumulation of aggregated proteins. Known as amyloid, these fibrillar aggregates include proteins such as tau and amyloid-ß (Aß) in Alzheimer's disease (AD) and alpha-synuclein (αSyn) in Parkinson's disease (PD). The development and spread of amyloid fibrils within the brain correlates with disease onset and progression, and inhibiting amyloid formation is a possible route toward therapeutic development. Recent advances have enabled the determination of amyloid fibril structures to atomic-level resolution, improving the possibility of structure-based inhibitor design. In this work, we use these amyloid structures to design inhibitors that bind to the ends of fibrils, "capping" them so as to prevent further growth. Using de novo protein design, we develop a library of miniprotein inhibitors of 35 to 48 residues that target the amyloid structures of tau, Aß, and αSyn. Biophysical characterization of top in silico designed inhibitors shows they form stable folds, have no sequence similarity to naturally occurring proteins, and specifically prevent the aggregation of their targeted amyloid-prone proteins in vitro. The inhibitors also prevent the seeded aggregation and toxicity of fibrils in cells. In vivo evaluation reveals their ability to reduce aggregation and rescue motor deficits in Caenorhabditis elegans models of PD and AD.
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Péptidos beta-Amiloides/antagonistas & inhibidores , Agregación Patológica de Proteínas/tratamiento farmacológico , alfa-Sinucleína/antagonistas & inhibidores , Proteínas tau/antagonistas & inhibidores , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Amiloide/química , Péptidos beta-Amiloides/metabolismo , Amiloidosis , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Agregación Patológica de Proteínas/metabolismo , alfa-Sinucleína/metabolismo , Proteínas tau/químicaRESUMEN
BACKGROUND: Despite research on the molecular bases of Alzheimer's disease (AD), effective therapies against its progression are still needed. Recent studies have shown direct links between AD progression and neurovascular dysfunction, highlighting it as a potential target for new therapeutics development. In this work, we screened and evaluated the inhibitory effect of natural compounds from native Peruvian plants against tau protein, amyloid beta, and angiotensin II type 1 receptor (AT1R) pathologic AD markers. METHODS: We applied in silico analysis, such as virtual screening, molecular docking, molecular dynamics simulation (MD), and MM/GBSA estimation, to identify metabolites from Peruvian plants with inhibitory properties, and compared them to nicotinamide, telmisartan, and grapeseed extract drugs in clinical trials. RESULTS: Our results demonstrated the increased bioactivity of three plants' metabolites against tau protein, amyloid beta, and AT1R. The MD simulations indicated the stability of the AT1R:floribundic acid, amyloid beta:rutin, and tau:brassicasterol systems. A polypharmaceutical potential was observed for rutin due to its high affinity to AT1R, amyloid beta, and tau. The metabolite floribundic acid showed bioactivity against the AT1R and tau, and the metabolite brassicasterol showed bioactivity against the amyloid beta and tau. CONCLUSIONS: This study has identified molecules from native Peruvian plants that have the potential to bind three pathologic markers of AD.
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Enfermedad de Alzheimer/tratamiento farmacológico , Descubrimiento de Drogas , Fitoquímicos/farmacología , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/química , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Humanos , Simulación del Acoplamiento Molecular , Perú , Fitoquímicos/química , Plantas/química , Receptor de Angiotensina Tipo 1/metabolismo , Proteínas tau/antagonistas & inhibidores , Proteínas tau/metabolismoRESUMEN
Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide. The association between AD and other diseases such as diabetes is well-studied. In parallel, potential disease-modifying effects of therapeutic agents used for diabetes have been investigated in the context AD of. Metformin is a biguanide and the most commonly prescribed medication for type 2 diabetes Due to its pleiotropic properties, metformin's potential disease-modifying effects are widely studied on different pathophysiological plyers of AD such as amyloid-ß (Aß) production and clearance, tau phosphorylation, and neuroinflammation, in relevant in vitro and in vivo models. In this review, we summarize the relevant scientific literature on the effects of metformin on various aspects of AD pathophysiology.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hipoglucemiantes/farmacología , Metformina/farmacología , Fosforilación/efectos de los fármacos , Fosforilación/fisiología , Placa Amiloide/tratamiento farmacológico , Placa Amiloide/metabolismo , Proteínas tau/antagonistas & inhibidores , Proteínas tau/metabolismoRESUMEN
Quinazolines are considered as a promising class of bioactive heterocyclic compounds with broad properties. Particularly, the quinazoline scaffold has an impressive role in the design and synthesis of new CNS-active drugs. The drug-like properties and pharmacological characteristics of quinazoline could lead to different drugs with various targets. Among CNS disorders, Alzheimer's disease (AD) is a progressive neurodegenerative disorder with memory loss, cognitive decline and language dysfunction. AD is a complex and multifactorial disease therefore, the need for finding multi-target drugs against this devastative disease is urgent. A literature survey revealed that quinazoline derivatives have diverse therapeutic potential for AD as modulators/inhibitors of ß-amyloid, tau protein, cholinesterases, monoamine oxidases, and phosphodiesterases as well as other protective effects. Thus, we describe here the most relevant and recent studies about anti-AD agents with quinazoline structure which can further aid the development and discovery of new anti-AD agents.