RESUMEN
Aberrant protein aggregation leads to the formation of amyloid fibrils. This phenomenon is linked to the development of more than 40 irremediable diseases such as Alzheimer's disease, Parkinson's disease, type 2 diabetes, and cancer. Plenty of research efforts have been given to understanding the underlying mechanism of protein aggregation, associated toxicity, and the development of amyloid inhibitors. Recently, the peptidomimetic approach has emerged as a potential tool to modulate several protein-protein interactions (PPIs). In this review, we discussed selected peptidomimetic-based approaches for the modulation of important amyloid proteins (Islet Amyloid Polypeptide, Amyloid Beta, α-synuclein, mutant p53, and insulin) aggregation. This approach holds a powerful platform for creating an essential stepping stone for the vital development of anti-amyloid therapeutic agents.
Asunto(s)
Proteínas Amiloidogénicas , Peptidomiméticos , Agregado de Proteínas , Humanos , alfa-Sinucleína/metabolismo , Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Proteínas Amiloidogénicas/química , Proteínas Amiloidogénicas/efectos de los fármacos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Peptidomiméticos/farmacología , Agregado de Proteínas/efectos de los fármacosRESUMEN
Transthyretin (TTR) is an amyloidogenic homotetramer involved in the transport of thyroxine and retinol in blood and cerebrospinal fluid. TTR stabilizers, such as tolcapone, an FDA approved drug for Parkinson's disease, are able to interact with residues of the thyroxine-binding sites of TTR, both wild type and pathogenic mutant forms, thereby stabilizing its tetrameric native state and inhibiting amyloidogenesis. Herein, we report on the synthesis of 3-deoxytolcapone, a novel stabilizer of TTR. The high-resolution X-ray analyses of the interactions of 3-O-methyltolcapone and 3-deoxytolcapone with TTR were performed. In the two TTR-ligand complexes the tolcapone analogues establish mainly H-bond and hydrophobic interactions with residues of the thyroxine-binding site of the TTR tetramer. Both compounds are capable of high and selective stabilization of TTR in the presence of plasma proteins, despite their markedly different 'forward' and 'reverse' binding mode, respectively. In fact, the loss or the weakening of stabilizing interactions with protein residues of 3-deoxytolcapone in comparison with tolcapone and 3-O-methyltolcapone is compensated by new interactions established at the dimer-dimer interface. Our data, coupled with previously reported data on the pharmacokinetics properties in humans of tolcapone and 3-O-methyltolcapone, further support the relevance of the latter tolcapone analogue as TTR stabilizer.
Asunto(s)
Proteínas Amiloidogénicas/efectos de los fármacos , Antiparkinsonianos/uso terapéutico , Tolcapona/análogos & derivados , Tolcapona/uso terapéutico , Antiparkinsonianos/farmacología , Humanos , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
Alzheimer's Disease (AD) is the most common neurodegenerative disease and cause of dementia. Characterized by amyloid plaques and neurofibrillary tangles of hyperphosphorylated Tau, AD pathology has been intensively studied during the last century. After a long series of failed trials of drugs targeting amyloid or Tau deposits, currently, hope lies in the positive results of one Phase III trial, highly debated, and on other ongoing trials. In parallel, some approaches target neuroinflammation, another central feature of AD. Therapeutic strategies are initially evaluated on animal models, in which the various drugs have shown effects on the target (decreasing amyloid, Tau and neuroinflammation) and sometimes on cognitive impairment. However, it is important to keep in mind that rodent models have a less complex brain than humans and that the pathology is generally not fully represented. Although they are indispensable tools in the drug discovery process, results obtained from animal models must be viewed with caution. In this review, we focus on the current status of disease-modifying therapies targeting amyloid, Tau and neuroinflammation with particular attention on the discrepancy between positive preclinical results on animal models and failures in clinical trials.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Placa Amiloide/tratamiento farmacológico , Proteínas tau/efectos de los fármacos , Proteínas Amiloidogénicas/efectos de los fármacos , Humanos , Ovillos Neurofibrilares/efectos de los fármacos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Depression is also common with older age. Alzheimer's disease (AD) studies suggest that both cerebrospinal fluid and positron emission tomography (PET) amyloid biomarkers are associated with more depressive symptoms in cognitively normal older adults. The recent availability of tau radiotracers offers the ability to examine in vivo tauopathy. It is unclear if the tau biomarker is associated with depression diagnosis. OBJECTIVE: We examined if tau and amyloid imaging were associated with a depression diagnosis among cognitively normal adults (Clinical Dementia Ratingâ=â0) and whether antidepressants modified this relationship. METHODS: Among 301 participants, logistic regression models evaluated whether in vivo PET tau was associated with depression, while another model tested the interaction between PET tau and antidepressant use. A second set of models substituted PET amyloid for PET tau. A diagnosis of depression (yes/no) was made during an annual clinical assessment by a clinician. Antidepressant use (yes/no) was determined by comparing medications the participants used to a list of 30 commonly used antidepressants. All models adjusted for age, sex, education, race, and apolipoprotein É4. Similar models explored the association between the biomarkers and depressive symptoms. RESULTS: Participants with elevated tau were twice as likely to be depressed. Antidepressant use modified this relationship where participants with elevated tau who were taking antidepressants had greater odds of being depressed. Relatedly, elevated amyloid was not associated with depression. CONCLUSIONS: Our results demonstrate that tau, not amyloid, was associated with a depression diagnosis. Additionally, antidepressant use interacts with tau to increase the odds of depression among cognitively normal adults.
Asunto(s)
Proteínas Amiloidogénicas/metabolismo , Encéfalo/patología , Depresión/patología , Proteínas tau/metabolismo , Anciano , Anciano de 80 o más Años , Proteínas Amiloidogénicas/efectos de los fármacos , Antidepresivos/uso terapéutico , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Estudios Transversales , Depresión/diagnóstico por imagen , Depresión/tratamiento farmacológico , Femenino , Humanos , Modelos Logísticos , Masculino , Pruebas de Estado Mental y Demencia , Persona de Mediana Edad , Neuroimagen , Tomografía de Emisión de Positrones , Escalas de Valoración Psiquiátrica , Proteínas tau/efectos de los fármacosRESUMEN
The global transcription factor, p53, is a master regulator of gene expression in cells. Mutations in the TP53 gene promote unregulated cell growth through the inactivation of downstream effectors of the p53 pathway. In fact, mutant p53 is highly prone to misfolding and frequently resides inside the cell as large aggregates, causing loss of physiological function of the tumor-suppressor protein. Here, we review the plausible reasons for functional loss of p53, including amyloid formation leading to unhindered cancer progression. We discuss previous as well as recent findings regarding the amyloid formation of p53 in vitro and in vivo. We elaborate on prion-like properties of p53 amyloids and their possible involvement in cancer progression. Because the p53 pathway is historically most targeted for the development of anticancer therapeutics, we have also summarized some of the recent approaches and advances in reviving the antiproliferative activities of wild-type p53. In this Perspective, we provide insight into understanding p53 as a prion-like protein and propose cancer to be recognized as an amyloid or prion-like disease.
Asunto(s)
Proteínas Amiloidogénicas/metabolismo , Neoplasias/etiología , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Amiloidogénicas/efectos de los fármacos , Animales , Antineoplásicos/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , Agregado de Proteínas/efectos de los fármacos , Conformación Proteica/efectos de los fármacos , Multimerización de Proteína/efectos de los fármacos , Proteína p53 Supresora de Tumor/efectos de los fármacosRESUMEN
A host of human diseases, including Parkinson's disease and Dementia with Lewy bodies, are suspected to be directly linked to protein aggregation. Amyloid protein aggregates and oligomeric intermediates of α-synuclein are observed in synucleinopathies and considered to be mediators of cellular toxicity. Hence, α-synuclein has seen as one of the leading and most compelling targets and is receiving a great deal of attention from researchers. Nevertheless, there is no neuroprotective approach directed toward Parkinson's disease or other synucleinopathies so far. In this review, we summarize the available data concerning inhibitors of α-synuclein aggregation and their advancing towards clinical use. The compounds are grouped according to their chemical structures, providing respective insights into their mechanism of action, pharmacology, and pharmacokinetics. Overall, shared structure-activity elements are emerging, as well as specific binding modes related to the ability of the modulators to establish hydrophobic and hydrogen bonds interactions with the protein. Some molecules with encouraging in vivo data support the possibility of translation to the clinic.
Asunto(s)
Proteínas Amiloidogénicas/efectos de los fármacos , Descubrimiento de Drogas , Agregación Patológica de Proteínas/tratamiento farmacológico , alfa-Sinucleína/antagonistas & inhibidores , Proteínas Amiloidogénicas/metabolismo , Humanos , Relación Estructura-Actividad , alfa-Sinucleína/metabolismoRESUMEN
PURPOSE: Observational studies have frequently reported that low blood folate concentrations are associated with poor cognitive performance. Our previous studies have shown the potential beneficial effect on the metabolite levels of methionine cycle and peripheral blood inflammatory cytokines from 6- and 12-month folic acid supplementation on cognitive function in mild cognitive impairment (MCI). This study aims to continue exploring the effect of 24-month folic acid supplementation on cognitive function and pathological mechanism in MCI. METHODS: 180 individuals with MCI were identified and randomly divided into intervention (folic acid 400 µg/day, n = 90) and convention (n = 90) groups. Cognitive function (WAIS-RC) and blood Aß-related biomarkers were measured at baseline and at 6, 12, 18, and 24 months. Data were analyzed using generalized estimating equation. This trial has been registered with Trial Number: ChiCTR-TRC-13003227. RESULTS: During the follow-up, scores of full scale IQ, verbal IQ, and subdomains of Information and Digit Span were significantly higher in the intervention group than those in the convention group (P < 0.05). In the intervention group, blood homocysteine, S-adenosylhomocysteine (SAH), Aß-42, and the expression of APP-mRNA were decreased (P < 0.05), while S-adenosylmethionine (SAM), SAM/SAH ratio, and the expression of DNA methyltransferase mRNA were increased (P < 0.05). CONCLUSION: Folic acid supplementation appears to improve cognitive function and reduce blood levels of Aß-related biomarkers in MCI. Larger-scale double-blind placebo-controlled randomized trials of longer duration are needed.
Asunto(s)
Disfunción Cognitiva/sangre , Disfunción Cognitiva/tratamiento farmacológico , Suplementos Dietéticos , Ácido Fólico/farmacología , Anciano , Proteínas Amiloidogénicas/sangre , Proteínas Amiloidogénicas/efectos de los fármacos , Biomarcadores/sangre , Análisis por Conglomerados , Cognición/efectos de los fármacos , Metilación de ADN/efectos de los fármacos , Femenino , Estudios de Seguimiento , Humanos , MasculinoRESUMEN
Several neurodegenerative diseases have a common pathophysiology where selective damage to neurons results from the accumulation of amyloid oligomer proteins formed via fibrilization. Considering that the formation of amyloid oligomers leads to cytotoxicity, the development of chemical compounds that are able to effectively cross the blood-brain barrier (BBB) and inhibit this conversion to oligomers and/or fibrils is essential for neurodegenerative disease therapy. We previously reported that pyrroloquinoline quinone (PQQ) prevented aggregation and fibrillation of α-synuclein, amyloid ß1-42 (Aß1-42), and mouse prion protein. To develop a novel drug against neurodegenerative diseases based on PQQ, it is necessary to improve the insufficient BBB permeability of PQQ. Here, we show that an esterified compound of PQQ, PQQ-trimethylester (PQQ-TME), has twice the BBB permeability than PQQ in vitro. Moreover, PQQ-TME exhibited greater inhibitory activity against fibrillation of α-synuclein, Aß1-42, and prion protein. These results indicated that esterification of PQQ could be a useful approach in developing a novel PQQ-based amyloid inhibitor.
Asunto(s)
Péptidos beta-Amiloides/efectos de los fármacos , Amiloide/efectos de los fármacos , Proteínas Amiloidogénicas/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Neuronas/efectos de los fármacos , Cofactor PQQ/análogos & derivados , Fragmentos de Péptidos/efectos de los fármacos , Proteínas Priónicas/efectos de los fármacos , Agregación Patológica de Proteínas/metabolismo , alfa-Sinucleína/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Esterificación , Ésteres/síntesis química , Ésteres/farmacología , Humanos , Ratones , Neuronas/metabolismo , Cofactor PQQ/síntesis química , Cofactor PQQ/farmacología , Fragmentos de Péptidos/metabolismo , Permeabilidad , Proteínas Priónicas/metabolismo , alfa-Sinucleína/metabolismoRESUMEN
Abnormal misfolding and aggregation of amyloid peptides into amyloid fibrils are common and critical pathological events in many neurodegenerative diseases. Most inhibitors or drugs have been developed to prevent amyloid aggregation of a specific peptide, showing sequence-dependent inhibition mechanisms. It is more challenging to develop or discover inhibitors capable of preventing the aggregation of two or more different amyloid peptides. Genistein, a major phytoestrogen in soybean, has been widely used as an anti-inflammation and cerebrovascular drug due to its antioxidation and antiacetylcholinesterase effects. Herein, we examine the inhibitory effects of genistein on the aggregation of amyloid-ß (Aß, associated with Alzheimer's disease) and human islet amylin (hIAPP, associated with type 2 diabetes) and Aß- and hIAPP-induced neurotoxicity using a combination of experimental and computational approaches. Collective experimental results from thioflavin T (ThT), atomic force microscopy (AFM), and circular dichroism (CD) demonstrate that genistein shows strong inhibition ability to prevent the conformational transition of both Aß and hIAPP monomers to ß-sheet structures, thus reducing final amyloid fibrillization from Aß and hIAPP monomer aggregation by 40-63%. Further 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH), and large unilamellar vesicle (LUV) assays show that genistein helps to increase cell viability, decrease cell apoptosis, and reduce cell membrane leakage, where the cell protection effect of genistein is likely correlated with its reduced membrane leakage. Comparative molecular dynamics (MD) simulations reveal that genistein prefers to bind the ß-sheet groove, a common structural motif of amyloid fibrils, of both Aß and hIAPP oligomers to interfere with their self-aggregation. This work for the first time demonstrates genistein as a dual inhibitor of Aß and hIAPP aggregation. Further structural optimization and refinement of genistein may generate a series of effective sequence-independent inhibitors against the aggregation and toxicity of different amyloid peptides.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Genisteína/farmacología , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Proteínas Amiloidogénicas/efectos de los fármacos , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Simulación de Dinámica MolecularRESUMEN
Heparan sulfates (HSs) modulate tissue elasticity in physiopathological conditions by interacting with various matrix constituents as tropoelastin and elastin-derived peptides. HSs bind also to protein moieties accelerating amyloid formation and influencing cytotoxic properties of insoluble fibrils. Interestingly, amyloidogenic polypeptides, despite their supposed pathogenic role, have been recently explored as promising bio-nanomaterials due to their unique and interesting properties. Therefore, we investigated the interactions of HSs, obtained from different sources and exhibiting various degree of sulfation, with synthetic amyloidogenic elastin-like peptides (ELPs), also looking at the effects of these interactions on cell viability and cell behavior using in vitro cultured fibroblasts, as a prototype of mesenchymal cells known to modulate the soft connective tissue environment. Results demonstrate, for the first time, that HSs, with differences depending on their sulfation pattern and chain length, interact with ELPs accelerating aggregation kinetics and amyloid-like fibril formation as well as self-association. Furthermore, these fibrils do not negatively affect fibroblasts' cell growth and parameters of redox balance, and influence cellular adhesion properties. Data provide information for a better understanding of the interactions altering the elastic component in aging and in pathologic conditions and may pave the way for the development of composite matrix-based biomaterials.
Asunto(s)
Amiloide/efectos de los fármacos , Proteínas Amiloidogénicas/efectos de los fármacos , Heparitina Sulfato/farmacología , Secuencia de Aminoácidos , Amiloide/química , Proteínas Amiloidogénicas/química , Animales , Células 3T3 BALB , Técnicas de Cultivo de Célula , Tejido Conectivo , Elasticidad/efectos de los fármacos , Elastina/química , Elastina/efectos de los fármacos , Elastina/metabolismo , Fibroblastos/química , Fibroblastos/metabolismo , Heparitina Sulfato/química , Heparitina Sulfato/metabolismo , Ratones , Péptidos/química , Conformación Proteica , Tropoelastina/químicaRESUMEN
Inhibiting the amyloid aggregation is considered to be an effective strategy to explore possible treatment of amyloid-related diseases including Alzheimer's disease, Parkinson's disease, and type II diabetes. Herein, a new high-efficiency and low-cytotoxicity Aß aggregation inhibitors, GQD-T, was designed through the combination of two Aß aggregation inhibitors, graphene quantum dots (GQDs) and tramiprosate. GQD-T showed the capability of efficiently inhibiting the aggregation of Aß peptides and rescuing Aß-induced cytotoxicity due to the synergistic effect of the GQDs and tramiprosate. In addition, the GQD-T has the characteristics of low toxicity and great biocompatibility. It is believed that GQD-T may be a potential candidate for an Alzheimer's drug and this work provides a new strategy for exploring Aß peptide aggregation inhibitors.
Asunto(s)
Péptidos beta-Amiloides/efectos de los fármacos , Amiloidosis/tratamiento farmacológico , Grafito/metabolismo , Puntos Cuánticos/metabolismo , Taurina/análogos & derivados , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Proteínas Amiloidogénicas/efectos de los fármacos , Proteínas Amiloidogénicas/metabolismo , Amiloidosis/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Humanos , Fragmentos de Péptidos/efectos de los fármacos , Fragmentos de Péptidos/metabolismo , Taurina/farmacologíaRESUMEN
Mitochondrial dysfunction is an early prominent feature in susceptible neurons in the brain of patients with Alzheimer's disease, which likely plays a critical role in the pathogenesis of disease. Increasing evidence suggests abnormal mitochondrial dynamics as important underlying mechanisms. In this study, we characterized marked mitochondrial fragmentation and abnormal mitochondrial distribution in the pyramidal neurons along with mitochondrial dysfunction in the brain of Alzheimer's disease mouse model CRND8 as early as 3 months of age before the accumulation of amyloid pathology. To establish the pathogenic significance of these abnormalities, we inhibited mitochondrial fragmentation by the treatment of mitochondrial division inhibitor 1 (mdivi-1), a mitochondrial fission inhibitor. Mdivi-1 treatment could rescue both mitochondrial fragmentation and distribution deficits and improve mitochondrial function in the CRND8 neurons both in vitro and in vivo. More importantly, the amelioration of mitochondrial dynamic deficits by mdivi-1 treatment markedly decreased extracellular amyloid deposition and Aß1-42/Aß1-40 ratio, prevented the development of cognitive deficits in Y-maze test and improved synaptic parameters. Our findings support the notion that abnormal mitochondrial dynamics plays an early and causal role in mitochondrial dysfunction and Alzheimer's disease-related pathological and cognitive impairments in vivo and indicate the potential value of restoration of mitochondrial dynamics as an innovative therapeutic strategy for Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Mitocondrias/fisiología , Dinámicas Mitocondriales/efectos de los fármacos , Enfermedad de Alzheimer/prevención & control , Péptidos beta-Amiloides/metabolismo , Proteínas Amiloidogénicas/efectos de los fármacos , Proteínas Amiloidogénicas/metabolismo , Animales , Encéfalo/metabolismo , Trastornos del Conocimiento/fisiopatología , Modelos Animales de Enfermedad , Ratones , Proteínas Mitocondriales/metabolismo , Neuronas/metabolismo , Células Piramidales/metabolismo , Células Piramidales/fisiología , Quinazolinonas/farmacologíaRESUMEN
Acinetobacter baumannii, opportunistic nosocomial pathogen, increases gradually in the clinical setup. The high level of resistance mechanisms acquired by these bacteria makes their eradication difficult and biofilm formation is one of them. Biofilm comprises of closely packed bacterial population crowded together by extra-cellular matrix (ECM). ECM contains bacterial secreted polymers such as exopolysaccharides (EPS), proteins and extracellular-DNA (e-DNA) and rarely amyloidogenic proteins. Biofilm offers protection of underlying bacterial population against chemotherapeutic agents and host immune system. Therefore, present efforts are focused to find a novel therapeutic that targets biofilm-associated infections. Plants are used as a natural therapeutic for numerous ailments. In order to find an alternative of the available antibacterial drugs, we have focused on the natural herbal active compounds. In this study, we have extracted active compounds from various medicinal plants and screened its anti-biofilm activity against carbapenem resistant strain of A. baumannii. Results showed that polar extract of kiwi (Actinidia deliciosa) and clove (Syzygium aromaticum) exhibit effective anti-biofilm activity. These two plants were also used for their phytochemical screening and TLC profiling to find out the constituting secondary metabolites. Actinidia deliciosa extract contains an alkaloid (sanquinarine) as well as a flavonoid (hydroxyflavone). Anti-biofilm effect of this extract on the ECM of A. baumannii showed that it reduces EPS, protein and eDNA contents in the ECM. Proteins of ECM have also shown to form amyloid like structure, which was evident from its interaction with the Congo Red. CFU counting after Actinidia deliciosa extract treatment also supported the results. Therefore, it can be concluded that polar extract of A. deliciosa can be used to find suitable alternative therapeutic to control biofilm formation by carbapenem resistant strain of Acinetobacter baumannii.
Asunto(s)
Acinetobacter baumannii/efectos de los fármacos , Actinidia/química , Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Extractos Vegetales/farmacología , Metabolismo Secundario , Infecciones por Acinetobacter/tratamiento farmacológico , Infecciones por Acinetobacter/microbiología , Acinetobacter baumannii/crecimiento & desarrollo , Alcaloides/aislamiento & purificación , Alcaloides/farmacología , Proteínas Amiloidogénicas/efectos de los fármacos , Antibacterianos/química , Antibacterianos/uso terapéutico , Proteínas Bacterianas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Carbapenémicos/farmacología , Recuento de Colonia Microbiana , ADN Bacteriano/efectos de los fármacos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Flavonoides/farmacología , Pruebas de Sensibilidad Microbiana , Fitoquímicos/química , Fitoquímicos/farmacología , Extractos Vegetales/química , Extractos Vegetales/uso terapéutico , Polisacáridos Bacterianos/metabolismo , Syzygium/químicaRESUMEN
Organochlorine (OC) pesticides pose a significant environmental risk to wildlife and humans and have been associated with Alzheimer's disease (AD). This study aims to spectroscopically analyze brains from free-flying birds and link the results to OC exposure and consequent amyloid aggregation. As long-lived apex predators, predatory birds represent a sentinel species similar to humans. Therefore, the results have implications for both species and may also add to our understanding of the role OC pesticides play in the development of AD. Brains of wild Sparrowhawks were analyzed using ATR-FTIR and Raman spectroscopy and Congo red staining; results were correlated with OC pesticide concentrations in livers. Effects of OC exposure were sex- and age-dependent and associated alterations were seen in lipids and protein secondary structure. A shift from α-helix to ß-sheet conformation of proteins indicated that concentrations of OC pesticides >7.18 µg/g may lead to cerebral amyloid aggregation.
Asunto(s)
Proteínas Amiloidogénicas/efectos de los fármacos , Aves , Encéfalo/patología , Hidrocarburos Clorados/toxicidad , Plaguicidas/toxicidad , Animales , HígadoRESUMEN
The increasing prevalence of conformational diseases, including Alzheimer's disease, type 2 Diabetes Mellitus and Cancer, poses a global challenge at many different levels. It has devastating effects on the sufferers as well as a tremendous economic impact on families and the health system. In this work, we apply a cross-functional approach that combines ideas, concepts and technologies from several disciplines in order to study, in silico and in vitro, the role of a novel chemical chaperones family (NCHCHF) in processes of protein aggregation in conformational diseases. Given that Serum Albumin (SA) is the most abundant protein in the blood of mammals, and Bovine Serum Albumin (BSA) is an off-the-shelf protein available in most labs around the world, we compared the ligandability of BSA:NCHCHF with the interaction sites in the Human Islet Amyloid Polypeptide (hIAPP):NCHCHF, and in the amyloid pharmacophore fragments (Aß17-42 and Aß16-21):NCHCHF. We posit that the merging of this interaction sites is a meta-structure of pharmacophore which allows the development of chaperones that can prevent protein aggregation at various states from: stabilizing the native state to destabilizing oligomeric state and protofilament. Furthermore to stabilize fibrillar structures, thus decreasing the amount of toxic oligomers in solution, as is the case with the NCHCHF. The paper demonstrates how a set of NCHCHF can be used for studying and potentially treating the various physiopathological stages of a conformational disease. For instance, when dealing with an acute phase of cytotoxicity, what is needed is the recruitment of cytotoxic oligomers, thus chaperone F, which accelerates fiber formation, would be very useful; whereas in a chronic stage it is better to have chaperones A, B, C, and D, which stabilize the native and fibril structures halting self-catalysis and the creation of cytotoxic oligomers as a consequence of fiber formation. Furthermore, all the chaperones are able to protect and recondition the cerebellar granule cells (CGC) from the cytotoxicity produced by the hIAPP20-29 fragment or by a low potassium medium, regardless of their capacity for accelerating or inhibiting in vitro formation of fibers. In vivo animal experiments are required to study the impact of chemical chaperones in cognitive and metabolic syndromes.
Asunto(s)
Proteínas Amiloidogénicas/metabolismo , Chaperonas Moleculares/metabolismo , Péptidos beta-Amiloides/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Proteínas Amiloidogénicas/efectos de los fármacos , Animales , Sitios de Unión , Dicroismo Circular , Simulación por Computador , Descubrimiento de Drogas/métodos , Humanos , Técnicas In Vitro , Microscopía Electrónica de Transmisión , Chaperonas Moleculares/farmacología , Simulación del Acoplamiento Molecular , Fragmentos de Péptidos/efectos de los fármacos , Fragmentos de Péptidos/metabolismo , Agregación Patológica de Proteínas/tratamiento farmacológico , Albúmina Sérica/metabolismo , Albúmina Sérica/farmacología , Albúmina Sérica Bovina/metabolismo , Albúmina Sérica Bovina/farmacologíaRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disease hallmarked by extracellular Aß(1-42) containing plaques, and intracellular neurofibrillary tangles (NFT) containing hyperphosphorylated tau protein. Progressively, memory deficits and cognitive disabilities start to occur as these hallmarks affect hippocampus and frontal cortex, regions highly involved in memory. Connective tissue growth factor (CTGF) expression, which is high in the vicinity of Aß plaques and NFTs, was found to influence γ-secretase activity, the molecular crux in Aß(1-42) production. Tauroursodeoxycholic acid (TUDCA) is an endogenous bile acid that downregulates CTGF expression in hepatocytes and has been shown to possess therapeutic efficacy in neurodegenerative models. To investigate the possible in vivo therapeutic effects of TUDCA, we provided 0.4% TUDCA-supplemented food to APP/PS1 mice, a well-established AD mouse model. Six months of TUDCA supplementation prevented the spatial, recognition and contextual memory defects observed in APP/PS1 mice at 8 months of age. Furthermore, TUDCA-supplemented APP/PS1 mice displayed reduced hippocampal and prefrontal amyloid deposition. These effects of TUDCA supplementation suggest a novel mechanistic route for Alzheimer therapeutics.
Asunto(s)
Enfermedad de Alzheimer/complicaciones , Proteínas Amiloidogénicas/efectos de los fármacos , Colagogos y Coleréticos/farmacología , Trastornos del Conocimiento/prevención & control , Ácido Tauroquenodesoxicólico/farmacología , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Proteínas Amiloidogénicas/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Trastornos del Conocimiento/patología , Suplementos Dietéticos , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Transgénicos , Presenilina-1/genéticaRESUMEN
OBJECTIVE: Inhibiting Aß generation is a prime therapeutic goal for preventing or treating Alzheimer disease. Here we sought to identify any disease-modifying properties of an azaindolizinone derivative, spiro[imidazo[1,2-a]pyridine-3,2-idan]-2(3H)-one (ST101 or ZSET1446). METHODS: The effects of ST101 were studied in 3xTg-AD mice and young cynomolgus monkeys using a combination of biochemical and histological analyses. RESULTS: Here we describe that ST101 induces cleavage of APP protein at a novel site, generating a 17 kDa C-terminal fragment. This 17 kDa APP cleavage product does not appear to be a substrate for either α- or ß-secretase, and thus bypasses generation of Aß. ST101 is orally active, efficacious at low doses, improves memory function, and robustly reduces brain Aß in transgenic mice and nonhuman primates. INTERPRETATION: Using rodent and nonhuman primate models, we show that ST101 represents a novel class of small molecules that reduce central nervous system levels of Aß by inducing an alternate pathway of APP cleavage.