RESUMO
Alzheimer's disease (AD) is the most common type of human dementia and is responsible for over 60% of diagnosed dementia cases worldwide. Abnormal deposition of ß-amyloid and the accumulation of neurofibrillary tangles have been recognised as the two pathological hallmarks targeted by AD diagnostic imaging as well as therapeutics. With the progression of pathological studies, the two hallmarks and their related pathways have remained the focus of researchers who seek for AD diagnostic and therapeutic strategies in the past decades. In this work, we reviewed the development of the AD biomarkers and their corresponding target-specific small molecule drugs for both diagnostic and therapeutic applications, underlining their success, failure, and future possibilities.
Assuntos
Doença de Alzheimer , Amiloidose , Biomarcadores , Tauopatias , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/diagnóstico , Biomarcadores/metabolismo , Amiloidose/tratamento farmacológico , Amiloidose/diagnóstico , Amiloidose/metabolismo , Animais , Tauopatias/tratamento farmacológico , Tauopatias/metabolismo , Peptídeos beta-Amiloides/metabolismo , Bibliotecas de Moléculas Pequenas/uso terapêuticoRESUMO
Tauopathies such as Alzheimer's disease are characterized by aggregation and increased phosphorylation of the microtubule-associated protein tau. Tau's pathological changes are closely linked to neurodegeneration, making tau a prime candidate for intervention. We developed an approach to monitor pathological changes of aggregation-prone human tau in living neurons. We identified 2-phenyloxazole (PHOX) derivatives as putative polypharmacological small molecules that interact with tau and modulate tau kinases. We found that PHOX15 inhibits tau aggregation, restores tau's physiological microtubule interaction, and reduces tau phosphorylation at disease-relevant sites. Molecular dynamics simulations highlight cryptic channel-like pockets crossing tau protofilaments and suggest that PHOX15 binding reduces the protofilament's ability to adopt a PHF-like conformation by modifying a key glycine triad. Our data demonstrate that live-cell imaging of a tauopathy model enables screening of compounds that modulate tau-microtubule interaction and allows identification of a promising polypharmacological drug candidate that simultaneously inhibits tau aggregation and reduces tau phosphorylation.
Assuntos
Doença de Alzheimer , Tauopatias , Humanos , Tauopatias/tratamento farmacológico , Tauopatias/metabolismo , Proteínas tau/metabolismo , Microtúbulos/metabolismo , Doença de Alzheimer/metabolismo , Citoesqueleto/metabolismo , FosforilaçãoRESUMO
The accumulation of tau is a hallmark of several neurodegenerative diseases and is associated with neuronal hypoactivity and presynaptic dysfunction. Oral administration of the adenosine A1 receptor antagonist rolofylline (KW-3902) has previously been shown to reverse spatial memory deficits and to normalize the basic synaptic transmission in a mouse line expressing full-length pro-aggregant tau (TauΔK) at low levels, with late onset of disease. However, the efficacy of treatment remained to be explored for cases of more aggressive tauopathy. Using a combination of behavioral assays, imaging with several PET-tracers, and analysis of brain tissue, we compared the curative reversal of tau pathology by blocking adenosine A1 receptors in three mouse models expressing different types and levels of tau and tau mutants. We show through positron emission tomography using the tracer [18F]CPFPX (a selective A1 receptor ligand) that intravenous injection of rolofylline effectively blocks A1 receptors in the brain. Moreover, when administered to TauΔK mice, rolofylline can reverse tau pathology and synaptic decay. The beneficial effects are also observed in a line with more aggressive tau pathology, expressing the amyloidogenic repeat domain of tau (TauRDΔK) with higher aggregation propensity. Both models develop a progressive tau pathology with missorting, phosphorylation, accumulation of tau, loss of synapses, and cognitive decline. TauRDΔK causes pronounced neurofibrillary tangle assembly concomitant with neuronal death, whereas TauΔK accumulates only to tau pretangles without overt neuronal loss. A third model tested, the rTg4510 line, has a high expression of mutant TauP301L and hence a very aggressive phenotype starting at ~3 months of age. This line failed to reverse pathology upon rolofylline treatment, consistent with a higher accumulation of tau-specific PET tracers and inflammation. In conclusion, blocking adenosine A1 receptors by rolofylline can reverse pathology if the pathological potential of tau remains below a threshold value that depends on concentration and aggregation propensity.
Assuntos
Receptor A1 de Adenosina , Tauopatias , Camundongos , Animais , Camundongos Transgênicos , Receptor A1 de Adenosina/genética , Receptor A1 de Adenosina/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo , Hipocampo/metabolismo , Tauopatias/tratamento farmacológico , Tauopatias/genética , Tauopatias/metabolismo , Cognição , Modelos Animais de DoençasRESUMO
Protein kinases (PKs) have emerged as one of the most intensively investigated drug targets in current pharmacological research, with indications ranging from oncology to neurodegeneration. Tau protein hyperphosphorylation was the first pathological post-translational modification of tau protein described in Alzheimer's disease (AD), highlighting the role of PKs in neurodegeneration. The therapeutic potential of protein kinase inhibitors (PKIs)) and protein phosphatase 2 A (PP2A) activators in AD has recently been explored in several preclinical and clinical studies with variable outcomes. Where a number of preclinical studies demonstrate a visible reduction in the levels of phospho-tau in transgenic tauopathy models, no reduction in neurofibrillary lesions is observed. Amongst the few PKIs and PP2A activators that progressed to clinical trials, most failed on the efficacy front, with only a few still unconfirmed and potential positive trends. This suggests that robust preclinical and clinical data is needed to unequivocally evaluate their efficacy. To this end, we take a systematic look at the results of preclinical and clinical studies of PKIs and PP2A activators, and the evidence they provide regarding the utility of this approach to evaluate the potential of targeting tau hyperphosphorylation as a disease modifying therapy.
Assuntos
Doença de Alzheimer , Tauopatias , Humanos , Doença de Alzheimer/metabolismo , Proteínas tau/metabolismo , Fosforilação , Tauopatias/tratamento farmacológico , Proteína Fosfatase 2 , Proteínas Quinases/metabolismoRESUMO
INTRODUCTION: Tauopathies represent clinicopathological entities with increased and abnormal glial and/or neuronal inclusions of tau, a microtubule-binding protein. Antisense oligonucleotides (ASOs) are a promising therapeutic approach for treating tauopathies as they can target tau mRNA to reduce total human tau expression or tau exon 10 expression and 4 R tau. Additionally, targeting the tau specifically with peptides may be a unique pharmacological approach, between small molecules and proteins. AREAS COVERED: The present review investigates the chemical basis of designing ASOs and peptides currently known to treat tauopathies. Among ASOs targeting tau expression, BIIB080 was the first to enter clinical trial development for treating mild Alzheimer's disease (AD). Furthermore, the therapeutic potential of peptide 021 (P021, Ac-DGGLAG-NH2) in tauopathies is discussed based on preclinical studies. EXPERT OPINION: ASOs are a promising therapeutic approach for tauopathies, particularly because ASOs may suppress the expression of harmful genes and are directly delivered to the brain, showing little systemic side effects. However, whether a generalized brain tau decrease will produce positive clinical effects remains unclear. A Phase II trial of BIIB080 is ongoing in mild AD. Neurotrophic and neurogenic peptide mimetic compounds have also shown potential as treatment options for AD and other tauopathies.
Assuntos
Doença de Alzheimer , Tauopatias , Humanos , Proteínas tau/metabolismo , Oligonucleotídeos/farmacologia , Tauopatias/tratamento farmacológico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Peptídeos/farmacologiaRESUMO
Tau oligomers play critical roles in tau pathology and are responsible for neuronal cell death and transmitting the disease in the brain. Accordingly, preventing tau oligomerization has become an important therapeutic strategy to treat tauopathies, including Alzheimer's disease. However, progress has been slow because detecting tau oligomers in the cellular context is difficult. Working toward tau-targeted drug discovery, our group has developed a tau-BiFC platform to monitor and quantify tau oligomerization. By using the tau-BiFC platform, we screened libraries with FDA-approved and passed phase I drugs and identified levosimendan as a potent anti-tau agent that inhibits tau oligomerization. 14C-isotope labeling of levosimendan revealed that levosimendan covalently bound to tau cysteines, directly inhibiting disulfide-linked tau oligomerization. In addition, levosimendan disassembles tau oligomers into monomers, rescuing neurons from aggregation states. In comparison, the well-known anti-tau agents methylene blue and LMTM failed to protect neurons from tau-mediated toxicity, generating high-molecular-weight tau oligomers. Levosimendan displayed robust potency against tau oligomerization and rescued cognitive declines induced by tauopathy in the TauP301L-BiFC mouse model. Our data present the potential of levosimendan as a disease-modifying drug for tauopathies.
Assuntos
Doença de Alzheimer , Tauopatias , Camundongos , Animais , Proteínas tau/metabolismo , Simendana/farmacologia , Simendana/uso terapêutico , Simendana/metabolismo , Tauopatias/tratamento farmacológico , Tauopatias/metabolismo , Tauopatias/patologia , Doença de Alzheimer/metabolismo , Neurônios/metabolismo , Modelos Animais de Doenças , Camundongos TransgênicosRESUMO
Alzheimer's disease and other tauopathies are the world's leading causes of dementia and memory loss. These diseases are thought to be caused by the misfolding and aggregation of the intracellular tau protein, ultimately leading to neurodegeneration. The tau protein is involved in a multitude of different neurodegenerative diseases. During the onset of tauopathies, tau undergoes structural changes and posttranslational modifications and aggregates into amyloid fibrils that are able to spread with a prion-like behavior. Up to now, there is no therapeutic agent which effectively controls or reverses the disease. Most of the therapeutics that were developed and underwent clinical trials targeted misfolded or aggregated forms of tau. In the current manuscript, we present the selection and characterization of two all D-enantiomeric peptides that bind monomeric tau protein with a low nanomolar KD, stabilize tau in its monomeric intrinsically disordered conformation, and stop the conversion of monomers into aggregates. We show that the effect of the two all D-enantiomeric peptides is strong enough to stop ongoing tau aggregation in vitro and is able to significantly reduce tau fibril assembly in cell culture. Both compounds may serve as new lead components for the development of therapeutic agents against Alzheimer's disease and other tauopathies.
Assuntos
Doença de Alzheimer , Tauopatias , Humanos , Proteínas tau/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Tauopatias/tratamento farmacológico , Tauopatias/metabolismo , Amiloide/metabolismo , Peptídeos/farmacologia , Peptídeos/uso terapêuticoRESUMO
Adenosine signals through four distinct G protein-coupled receptors that are located at various synapses, cell types and brain areas. Through them, adenosine regulates neuromodulation, neuronal signaling, learning and cognition as well as the sleep-wake cycle, all strongly impacted in neurogenerative disorders, among which Alzheimer's Disease (AD). AD is a complex form of cognitive deficits characterized by two pathological hallmarks: extracellular deposits of aggregated ß-amyloid peptides and intraneuronal fibrillar aggregates of hyper- and abnormally phosphorylated Tau proteins. Both lesions contribute to the early dysfunction and loss of synapses which are strongly associated to the development of cognitive decline in AD patients. The present review focuses on the pathophysiological impact of the A2ARs dysregulation observed in cognitive area from AD patients. We are reviewing not only evidence of the cellular changes in A2AR levels in pathological conditions but also describe what is currently known about their consequences in term of synaptic plasticity, neuro-glial miscommunication and memory abilities. We finally summarize the proof-of-concept studies that support A2AR as credible targets and the clinical interest to repurpose adenosine drugs for the treatment of AD and related disorders. This article is part of the Special Issue on "Purinergic Signaling: 50 years".
Assuntos
Doença de Alzheimer , Tauopatias , Humanos , Doença de Alzheimer/metabolismo , Adenosina , Tauopatias/tratamento farmacológico , Proteínas tau , Peptídeos beta-Amiloides/metabolismo , Receptor A2A de Adenosina/metabolismoRESUMO
BACKGROUND AND OBJECTIVE: Tauopathy is a group of neurodegenerative diseases in which the pathogenesis processes are related to tau protein. The imbalances between the activities of kinases and phosphatases of tau protein lead to tau hyperphosphorylation and subsequent neurodegeneration. Numerous studies suggest a strong linkage between type 2 diabetes mellitus (T2D) and neurodegenerative diseases. Therefore, finding a drug with a dual therapeutic activity against T2D and neuroprotective will be a promising idea. Hence, the potential neuroprotective effect of Glimepiride (GPD) against tauopathy was evaluated in the current study. METHODS: P301S mice model was employed for tauopathy and C57BL/6 wild type mice (WT) was used as control. Phosphorylated and acetylated tau protein levels was assessed in cortex and hippocampus by western blot. Effect of GPD on tauopathy related enzymes, neuroinflammation, apoptotic markers were evaluated. Furthermore, the neuroprotective effects against anxiety like behavior and motor impairment was analyzed using Parallel rod floor and Open field tests. RESULTS: GPD significantly ameliorates motor impairment, anxiety like behavior and neurodegeneration in P301S mice. Phosphorylated tau and acetylated tau were significantly decreased in both cortex and hippocampus of P301S mice via decreasing GSK3ß, increasing ratio of phosphorylated-AKT to total-AKT, increasing PP2A and normalization of CDK5 levels. Furthermore, GPD treatment also decreased neuroinflammation and apoptosis by reducing NF-kB, TNF-α and caspase 3 levels. CONCLUSION: The current data suggests that GPD exerts a protective effect against tauopathy, behavioural consequences, neurodegeneration, neuroinflammation and apoptosis. GPD is therefore a promising agent for the treatment of neurodegenerative diseases associated with tauopathy.
Assuntos
Diabetes Mellitus Tipo 2 , Doenças Neurodegenerativas , Fármacos Neuroprotetores , Tauopatias , Animais , Caspase 3 , Modelos Animais de Doenças , Glicogênio Sintase Quinase 3 beta , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NF-kappa B , Doenças Neuroinflamatórias , Fármacos Neuroprotetores/farmacologia , Monoéster Fosfórico Hidrolases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt , Compostos de Sulfonilureia , Tauopatias/tratamento farmacológico , Tauopatias/metabolismo , Tauopatias/patologia , Fator de Necrose Tumoral alfa , Proteínas tau/metabolismo , Proteínas tau/uso terapêuticoRESUMO
Advances in targeted regulation of gene expression allowed new therapeutic approaches for monogenic neurological diseases. Molecular diagnosis has paved the way to personalized medicine targeting the pathogenic roots: DNA or its RNA transcript. These antisense therapies rely on modified nucleotides sequences (single-strand DNA or RNA, both belonging to the antisense oligonucleotides family, or double-strand interfering RNA) to act specifically on pathogenic target nucleic acids, thanks to complementary base pairing. Depending on the type of molecule, chemical modifications and target, base pairing will lead alternatively to splicing modifications of primary transcript RNA or transient messenger RNA degradation or non-translation. The key to success for neurodegenerative diseases also depends on the ability to reach target cells. The most advanced antisense therapies under development in neurological disorders are presented here, at the clinical stage of development, either at phase 3 or market authorization stage, such as in spinal amyotrophy, Duchenne muscular dystrophy, transthyretin-related hereditary amyloidosis, porphyria and amyotrophic lateral sclerosis; or in earlier clinical phase 1 B, for Huntington's disease, synucleinopathies and tauopathies. We also discuss antisense therapies at the preclinical stage, such as in some tauopathies, spinocerebellar ataxias or other rare neurological disorders. Each subtype of antisense therapy, antisense oligonucleotides or interfering RNA, has proved target engagement or even clinical efficacy in patients; undisputable recent advances for severe and previously untreatable neurological disorders. Antisense therapies show great promise, but many unknowns remain. Expanding the initial successes achieved in orphan or rare diseases to other disorders will be the next challenge, as shown by the recent failure in Huntington disease or due to long-term preclinical toxicity in multiple system atrophy and cystic fibrosis. This will be critical in the perspective of new planned applications to premanifest mutation carriers, or other non-genetic degenerative disorders such as multiple system atrophy or Parkinson disease.
Assuntos
Doença de Huntington , Atrofia de Múltiplos Sistemas , Atrofia Muscular Espinal , Tauopatias , Humanos , Doença de Huntington/tratamento farmacológico , Oligonucleotídeos Antissenso/uso terapêutico , RNA , Tauopatias/tratamento farmacológicoRESUMO
Intrinsically disordered proteins (IDPs) play important roles in disease pathologies; however, their lack of defined stable 3D structures make traditional drug design strategies typically less effective against these targets. Based on promising results of targeted covalent inhibitors (TCIs) on challenging targets, we have developed a covalent design strategy targeting IDPs. As a model system we chose tau, an endogenous IDP of the central nervous system that is associated with severe neurodegenerative diseases via its aggregation. First, we mapped the tractability of available cysteines in tau and prioritized suitable warheads. Next, we introduced the selected vinylsulfone warhead to the non-covalent scaffolds of potential tau aggregation inhibitors. The designed covalent tau binders were synthesized and tested in aggregation models, and inhibited tau aggregation effectively. Our results revealed the usefulness of the covalent design strategy against therapeutically relevant IDP targets and provided promising candidates for the treatment of tauopathies.
Assuntos
Proteínas Intrinsicamente Desordenadas , Doenças Neurodegenerativas , Tauopatias , Cisteína , Desenho de Fármacos , Humanos , Proteínas Intrinsicamente Desordenadas/química , Doenças Neurodegenerativas/metabolismo , Tauopatias/tratamento farmacológico , Proteínas tau/metabolismoRESUMO
Tauopathy is a term that has been used to represent a pathological condition in which hyperphosphorylated tau protein aggregates in neurons and glia which results in neurodegeneration, synapse loss and dysfunction and cognitive impairments. Recently, drug repositioning strategy (DRS) becomes a promising field and an alternative approach to advancing new treatments from actually developed and FDA approved drugs for an indication other than the indication it was originally intended for. This paradigm provides an advantage because the safety of the candidate compound has already been established, which abolishes the need for further preclinical safety testing and thus substantially reduces the time and cost involved in progressing of clinical trials. In the present review, we focused on correlation between tauopathy and common diseases as type 2 diabetes mellitus and the global virus COVID-19 and how tau pathology can aggravate development of these diseases in addition to how these diseases can be a risk factor for development of tauopathy. Moreover, correlation between COVID-19 and type 2 diabetes mellitus was also discussed. Therefore, repositioning of a drug in the daily clinical practice of patients to manage or prevent two or more diseases at the same time with lower side effects and drug-drug interactions is a promising idea. This review concluded the results of pre-clinical and clinical studies applied on antidiabetics, COVID-19 medications, antihypertensives, antidepressants and cholesterol lowering drugs for possible drug repositioning for management of tauopathy.
Assuntos
Antivirais/farmacologia , COVID-19/fisiopatologia , Reposicionamento de Medicamentos , Hipoglicemiantes/farmacologia , Tauopatias/tratamento farmacológico , Antidepressivos/farmacologia , Anti-Hipertensivos/farmacologia , Apoptose/efeitos dos fármacos , Diabetes Mellitus Tipo 2/fisiopatologia , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Humanos , Terapia de Alvo Molecular/métodos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Tauopatias/fisiopatologia , Tratamento Farmacológico da COVID-19RESUMO
The human kinome plays a crucial role in several pathways. Its dysregulation has been linked to diverse central nervous system (CNS)-related disorders with a drastic impact on the aging population. Among them, tauopathies, such as Alzheimer's Disease (AD) and Frontotemporal Lobar degeneration (FTLD-tau), are neurodegenerative disorders pathologically defined by the presence of hyperphosphorylated tau-positive intracellular inclusions known as neurofibrillary tangles (NFTs). Compelling evidence has reported the great potential of the simultaneous modulation of multiple protein kinases (PKs) involved in abnormal tau phosphorylation through a concerted pharmacological approach to achieve a superior therapeutic effect relative to classic "one target, one drug" approaches. Here, we report on the identification and characterization of ARN25068 (4), a low nanomolar and well-balanced dual GSK-3ß and FYN inhibitor, which also shows inhibitory activity against DYRK1A, an emerging target in AD and tauopathies. Computational and X-Ray studies highlight compound 4's typical H-bonding pattern of ATP-competitive inhibitors at the binding sites of all three PKs. In a tau phosphorylation assay on Tau0N4R-TM-tGFP U2OS cell line, 4 reduces the extent of tau phosphorylation, promoting tau-stabilized microtubule bundles. In conclusion, this compound emerges as a promising prototype for further SAR explorations to develop potent and well-balanced triple GSK-3ß/FYN/DYRK1A inhibitors to tackle tau hyperphosphorylation.
Assuntos
Glicogênio Sintase Quinase 3 beta/metabolismo , Fármacos Neuroprotetores/síntese química , Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-fyn/antagonistas & inibidores , Tauopatias/tratamento farmacológico , Sítios de Ligação , Avaliação Pré-Clínica de Medicamentos , Humanos , Microtúbulos/metabolismo , Modelos Moleculares , Emaranhados Neurofibrilares/metabolismo , Fármacos Neuroprotetores/farmacologia , Fosforilação , Ligação Proteica , Conformação Proteica , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade , Proteínas tau/metabolismo , Quinases DyrkRESUMO
The application of photo-excited dyes for treatment is known as photodynamic therapy (PDT). PDT is known to target GTPase proteins in cells, which are the key proteins of diverse signalling cascades which ultimately modulate cell proliferation and death. Cytoskeletal proteins play critical roles in maintaining cell integrity and cell division. Whereas, it was also observed that in neuronal cells PDT modulated actin and tubulin resulting in increased neurite growth and filopodia. Recent studies supported the role of PDT in dissolving the extracellular amyloid beta aggregates and intracellular Tau aggregates, which indicated the potential role of PDT in neurodegeneration. The advancement in the field of PDT led to its clinical approval in treatment of cancers, brain tumour, and dermatological acne. Although several question need to be answered for application of PDT in neuronal cells, but the primary studies gave a hint that it can emerge as potential therapy in neural cells.
Assuntos
Fotoquimioterapia , Tauopatias , Humanos , GTP Fosfo-Hidrolases , Peptídeos beta-Amiloides , Fotoquimioterapia/métodos , Tauopatias/tratamento farmacológicoRESUMO
BACKGROUND: Tauopathies are a group of neurodegenerative disorders, including Alzheimer's disease (AD) and frontotemporal lobar degeneration with tau pathology. Hyperphosphorylation modification promotes tau protein misfolding and aggregation into neurofibrillary tangles, leading to impairments of synaptic plasticity and learning and memory. However, very limited therapeutic strategies are available. OBJECTIVE: In the present study, we wanted to investigate the potential effects of Dihydroartemisinin (DHA) on tauopathies. METHODS: We constructed adeno-associated virus carrying hTau cDNA (AAVhTau) to establish a mouse model of tauopathy through intrahippocampal microinjection. Using a combination of behavioral test, electrophysiological recording, and western blotting assay, we examined the neuroprotective effects of DHA on learning and memory deficits in mice with tauopathy. RESULTS: DHA improved learning and memory and increased hippocampal CA1 long-term potentiation (LTP) in mice overexpressed human tau (hTau) in the hippocampus. More importantly, further study revealed that DHA could induce protein O-GlcNAcylation modification and reduce protein phosphorylation. O-GlcNAc transferase inhibitor alloxan could suppress DHA-induced protein O-GlcNAcylation, and subsequently prevent therapeutic effect of DHA on the deficits of learning and memory as well as synaptic plasticity in hTau mice. CONCLUSION: These results indicate that DHA may exert neuroprotective role in tauopathy through a crosstalk between O-GlcNAcylation and phosphorylation, suggesting a potential therapeutic for learning and memory deficits associated with tau pathology.
Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Cognição/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Tauopatias/tratamento farmacológico , Doença de Alzheimer/patologia , Animais , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Aprendizagem/efeitos dos fármacos , Camundongos , FosforilaçãoRESUMO
A continuing challenge in modern medicine is the identification of safer and more efficacious drugs. Precision therapeutics, which have one molecular target, have been long promised to be safer and more effective than traditional therapies. This approach has proven to be challenging for multiple reasons including lack of efficacy, rapidly acquired drug resistance, and narrow patient eligibility criteria. An alternative approach is the development of drugs that address the overall disease network by targeting multiple biological targets ('polypharmacology'). Rational development of these molecules will require improved methods for predicting single chemical structures that target multiple drug targets. To address this need, we developed the Multi-Targeting Drug DREAM Challenge, in which we challenged participants to predict single chemical entities that target pro-targets but avoid anti-targets for two unrelated diseases: RET-based tumors and a common form of inherited Tauopathy. Here, we report the results of this DREAM Challenge and the development of two neural network-based machine learning approaches that were applied to the challenge of rational polypharmacology. Together, these platforms provide a potentially useful first step towards developing lead therapeutic compounds that address disease complexity through rational polypharmacology.
Assuntos
Desenvolvimento de Medicamentos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Tauopatias/tratamento farmacológico , Humanos , Neoplasias/metabolismo , Redes Neurais de Computação , Polifarmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
Neurodegenerative disorders, including Tauopathies that involve tau protein, base their pathological mechanism on forming proteinaceous aggregates, which has a deleterious effect on cells triggering an inflammatory response. Moreover, tau inhibitors can exert their mechanism of action through noncovalent and covalent interactions. Thus, Michael's addition appears as a feasible type of interaction involving an α, ß unsaturated carbonyl moiety to avoid pathological confirmation and further cytotoxicity. Moreover, we isolated three compounds from Antarctic lichens Cladonia cariosa and Himantormia lugubris: protolichesterinic acid (1), fumarprotocetraric acid (2), and lichesterinic acid (3). The maleimide cysteine labeling assay showed that compounds 1, 2, and 3 inhibit at 50 µM, but compounds 2 and 3 are statistically significant. Based on its inhibition capacity, we decided to test compound 2 further. Thus, our results suggest that compound 2 remodel soluble oligomers and diminish ß sheet content, as demonstrated through ThT experiments. Hence, we added externally treated oligomers with compound 2 to demonstrate that they are harmless in cell culture. First, the morphology of cells in the presence of aggregates does not suffer evident changes compared to the control. Additionally, the externally added aggregates do not provoke a substantial LDH release compared to the control, indicating that treated oligomers do not provoke membrane damage in cell culture compared with aggregates alone. Thus, in the present work, we demonstrated that Michael's acceptors found in lichens could serve as a scaffold to explore different mechanisms of action to turn tau aggregates into harmless species.
Assuntos
Fumaratos/farmacologia , Agregados Proteicos/efeitos dos fármacos , Proteínas tau/antagonistas & inibidores , Proteínas tau/metabolismo , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacologia , Regiões Antárticas , Ascomicetos/metabolismo , Linhagem Celular Tumoral , Humanos , Líquens/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Parmeliaceae/metabolismo , Tauopatias/tratamento farmacológico , Tauopatias/metabolismoRESUMO
Intraneuronal accumulation of hyperphosphorylated tau is a hallmark pathology shown in over twenty neurodegenerative disorders, collectively termed as tauopathies, including the most common Alzheimer's disease (AD). Therefore, selectively removing or reducing hyperphosphorylated tau is promising for therapies of AD and other tauopathies. Here, we designed and synthesized a novel DEPhosphorylation TArgeting Chimera (DEPTAC) to specifically facilitate the binding of tau to Bα-subunit-containing protein phosphatase 2A (PP2A-Bα), the most active tau phosphatase in the brain. The DEPTAC exhibited high efficiency in dephosphorylating tau at multiple AD-associated sites and preventing tau accumulation both in vitro and in vivo. Further studies revealed that DEPTAC significantly improved microtubule assembly, neurite plasticity, and hippocampus-dependent learning and memory in transgenic mice with inducible overexpression of truncated and neurotoxic human tau N368. Our data provide a strategy for selective removal of the hyperphosphorylated tau, which sheds new light for the targeted therapy of AD and related-tauopathies.
Assuntos
Doença de Alzheimer , Peptídeos , Proteína Fosfatase 2 , Tauopatias , Proteínas tau , Animais , Humanos , Camundongos , Ratos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Camundongos Transgênicos , Microtúbulos/efeitos dos fármacos , Microtúbulos/genética , Terapia de Alvo Molecular , Peptídeos/síntese química , Peptídeos/farmacologia , Fosforilação/efeitos dos fármacos , Cultura Primária de Células , Ligação Proteica/efeitos dos fármacos , Proteína Fosfatase 2/antagonistas & inibidores , Proteína Fosfatase 2/genética , Proteínas tau/genética , Tauopatias/tratamento farmacológico , Tauopatias/genética , Tauopatias/patologiaRESUMO
Since the role of estrogen in postmenauposal-associated dementia is still debatable, this issue urges the search for other medications. Dimethyl fumarate (DMF) is a drug used for the treatment of multiple sclerosis and has shown a neuroprotective effect against other neurodegenerative diseases. Accordingly, the present study aimed to evaluate the effect of DMF on an experimental model of Alzheimer disease (AD) using D-galactose (D-Gal) administered to ovariectomized (OVX) rats, resembling a postmenopausal dementia paradigm. Adult 18-month old female Wistar rats were allocated into sham-operated and OVX/D-Gal groups that were either left untreated or treated with DMF for 56 days starting three weeks after sham-operation or ovariectomy. DMF succeeded to ameliorate cognitive (learning/short- and long-term memory) deficits and to enhance the dampened overall activity (NOR, Barnes-/Y-maze tests). These behavioral upturns were associated with increased intact neurons (Nissl stain) and a reduction in OVX/D-Gal-mediated hippocampal CA1 neurodegeneration and astrocyte activation assessed as GFAP immunoreactivity. Mechanistically, DMF suppressed the hippocampal contents of AD-surrogate markers; viz., apolipoprotein (APO)-E1, BACE1, Aß42, and hyperphosphorylated Tau. Additionally, DMF has augmented the neuroprotective parameters p-AKT, its downstream target CREB and BDNF. Besides, it activated AMPK, and enhanced SIRT-1, as well as antioxidant defenses (SOD, GSH). On the other hand, DMF inhibited the transcription factor NF-κB, IL-1ß, adiponectin/adiponectin receptor type (AdipoR)1, GSK-3ß, and MDA. Accordingly, in this postmenopausal AD model, DMF treatment by pursuing the adiponectin/AdipoR1, AMPK/SIRT-1, AKT/CREB/BDNF, AKT/GSK-3ß, and APO-E1 quartet hampered the associated tauo-/amyloidopathy and NF-κB-mediated oxidative/inflammatory responses to advance insights into its anti-amnesic effect.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Amiloidose/tratamento farmacológico , Fumarato de Dimetilo/farmacologia , Fármacos Neuroprotetores/farmacologia , Ovariectomia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Tauopatias/tratamento farmacológico , Adiponectina/genética , Doença de Alzheimer/induzido quimicamente , Amiloidose/induzido quimicamente , Amiloidose/psicologia , Animais , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Feminino , Galactose , Glicogênio Sintase Quinase 3 beta/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/genética , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/efeitos dos fármacos , Proteína Oncogênica v-akt/efeitos dos fármacos , Proteína Oncogênica v-akt/genética , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio , Tauopatias/induzido quimicamente , Tauopatias/psicologiaRESUMO
Accumulation of pathological tau in synapses has been identified as an early event in Alzheimer's disease (AD) and correlates with cognitive decline in patients with AD. Tau is a cytosolic axonal protein, but under disease conditions, tau accumulates in postsynaptic compartments and presynaptic terminals, due to missorting within neurons, transsynaptic transfer between neurons, or a failure of clearance pathways. Using subcellular fractionation of brain tissue from rTg4510 tau transgenic mice with tauopathy and human postmortem brain tissue from patients with AD, we found accumulation of seed-competent tau predominantly in postsynaptic compartments. Tau-mediated toxicity in postsynaptic compartments was exacerbated by impaired proteasome activity detected by measuring lysine-48 polyubiquitination of proteins targeted for proteasomal degradation. To combat the accumulation of tau and proteasome impairment in the postsynaptic compartments of rTg4510 mouse brain, we stimulated the pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1R) with its ligand PACAP administered intracerebroventricularly to rTg4510 mice. We observed enhanced synaptic proteasome activity and reduced total tau in postsynaptic compartments in mouse brain after PACAP treatment. The clearance of tau from postsynaptic compartments correlated with attenuated tauopathy and improved cognitive performance of rTg4510 transgenic mice on two behavioral tests. These results suggest that activating PAC1R could prevent accumulation of aggregate-prone tau and indicate a potential therapeutic approach for AD and other tauopathies.