RESUMO
The original etiology of Alzheimer's disease (AD) is the deposition of amyloid-beta (Aß) proteins, which starts from the aggregation of the Aß oligomers. The optimal therapeutic strategy targeting Aß oligomer aggregation is the development of AD vaccines. Despite the fact that positive progress has been made for experimental attempts at AD vaccines, the physicochemical and even structural properties of these AD vaccines remain unclear. In this study, through immunoinformatic and molecular dynamics (MD) simulations, we first designed and simulated an alternative of vaccine TAPAS and found that the structure of the alternative can reproduce the 3D conformation of TAPAS determined experimentally. Meanwhile, immunoinformatic methods were used to analyze the physicochemical properties of TAPAS, including immunogenicity, antigenicity, thermal stability, and solubility, which confirm well the efficacy and safety of the vaccine, and validate the scheme reliability of immunoinformatic and MD simulations in designing and simulating the TAPAS vaccine. Using the same scheme, we predicted the 3D conformation of the optimized ACI-24 peptide vaccine, an Aß peptide with the first 15 residues of Aß42 (Aß1-15). The vaccine was verified once to be effective against both full-length Aß1-42 and truncated Aß4-42 aggregates, but an experimental 3D structure was absent. We have also explored the immune mechanism of the vaccine at the molecular level and found that the optimized ACI-24 and its analogues can block the growth of either full-length Aß1-42 or truncated Aß4-42 pentamer by contacting the hydrophobic residues within the N-terminus and ß1 region on the contact surface of either pentamer. Additionally, residues (D1, D7, S8, H13, and Q15) were identified as the key residues of the vaccine to contact either of the two Aß oligomers. This work provides a feasible implementation scheme of immunoinformatic and MD simulations for the development of AD small peptide vaccines, validating the power of the scheme as a parallel tool to the experimental approaches and injecting molecular-level information into the understanding and design of anti-AD vaccines.
Assuntos
Vacinas contra Alzheimer , Peptídeos beta-Amiloides , Fragmentos de Peptídeos , Vacinas de Subunidades Proteicas , Humanos , Doença de Alzheimer/prevenção & controle , Vacinas contra Alzheimer/química , Vacinas contra Alzheimer/imunologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/imunologia , Simulação de Dinâmica Molecular , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/imunologia , Conformação Proteica , Vacinas de Subunidades Proteicas/química , Vacinas de Subunidades Proteicas/imunologiaRESUMO
Alzheimer's disease (AD) is the most common neurodegeneration having non-effective treatments. Vaccines or monoclonal antibodies are two typical immunotherapies for AD. Due to Aß neurotoxicity, most of the treatments target its generation and deposition. However, therapies that specifically target tau protein are also being investigated. UB311 vaccine generates N-terminal anti-Aß antibodies, that neutralize Aß toxicity and promote plaque clearance. It is designed to elicit specific B-cell and wide T-cell responses. ACC001 or PF05236806 vaccine has the same Aß fragment and QS21 as an adjuvant. CAD106 stimulates response against Aß1-6. However, Nasopharyngitis and injection site erythema are its side effects. AN1792, the first-generation vaccine was formulated in proinflammatory QS21 adjuvant. However, T-cell epitopes are omitted from the developed epitope AD vaccine with Aß1-42B-cell epitopes. The first-generation vaccine immune response was immensely successful in clearing Aß, but it was also sufficient to provoke meningoencephalitis. Immunotherapies have been at the forefront of these initiatives in recent years. The review covers the recent updates on active and passive immunotherapy for AD.
Assuntos
Doença de Alzheimer , Vacinas contra Alzheimer , Peptídeos beta-Amiloides , Imunoterapia , Doença de Alzheimer/imunologia , Doença de Alzheimer/terapia , Humanos , Animais , Imunoterapia/métodos , Peptídeos beta-Amiloides/imunologia , Vacinas contra Alzheimer/imunologia , Vacinas contra Alzheimer/uso terapêutico , Imunização Passiva/métodos , Anticorpos Monoclonais/uso terapêutico , Imunoterapia Ativa/métodosRESUMO
Alzheimer's Disease (AD) is a progressive neurodegenerative disease strongly associated with increasing age. Neuroinflammation and the accumulation of amyloid protein are amongst the hallmarks of this disease and most translational research to date has focused on targeting these two processes. However, the exact etiology of AD remains to be fully elucidated. When compared alongside, the immune response in AD closely resembles the central nervous system (CNS) immune changes seen in elderly individuals. It is possible that AD is a pathological consequence of an aged immune system secondary to chronic stimulation by a previous or ongoing insult. Pathological changes like amyloid accumulation and neuronal cell death may reflect this process of immunosenescence as the CNS immune system fails to maintain homeostasis in the CNS. It is likely that future treatments designed to modulate the aged immune system may prove beneficial in altering the disease course. The development of new tests for appropriate biomarkers would also be essential in screening for patients most likely to benefit from such treatments.
Assuntos
Envelhecimento/imunologia , Doença de Alzheimer/imunologia , Encéfalo/imunologia , Imunossenescência , Neuroimunomodulação , Fatores Etários , Envelhecimento/metabolismo , Envelhecimento/patologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/terapia , Vacinas contra Alzheimer/uso terapêutico , Peptídeos beta-Amiloides/imunologia , Peptídeos beta-Amiloides/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Biomarcadores/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Humanos , Imunoterapia , Degeneração NeuralRESUMO
Alzheimer's disease (AD) is a global health concern owing to its complexity, which often poses a great challenge to the development of therapeutic approaches. No single theory has yet accounted for the various risk factors leading to the pathological and clinical manifestations of dementia-type AD. Therefore, treatment options targeting various molecules involved in the pathogenesis of the disease have been unsuccessful. However, the exploration of various immunotherapeutic avenues revitalizes hope after decades of disappointment. The hallmark of a good immunotherapeutic candidate is not only to remove amyloid plaques but also to slow cognitive decline. In line with this, both active and passive immunotherapy have shown success and limitations. Recent approval of aducanumab for the treatment of AD demonstrates how close passive immunotherapy is to being successful. However, several major bottlenecks still need to be resolved. This review outlines recent successes and challenges in the pursuit of an AD vaccine.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Vacinas contra Alzheimer , Anticorpos Monoclonais Humanizados/uso terapêutico , Imunoterapia , Disfunção Cognitiva/prevenção & controle , Humanos , Placa Amiloide/patologiaRESUMO
Alzheimer's disease is a common cause of dementia, for which no disease-modifying therapy is yet available. Aß3-10-KLH, a vaccine for active immunization, has been shown to prevent pathological changes in young transgenic models of AD, but the effects of treatment with it and its effects on mitochondrial dysfunction remain unclear. We immunized 6-month-old Tg-APPswe/PSEN1dE9 mice with Aß3-10-KLH to analyze whether it is capable of eliminating amyloid-ß after its appearance. The vaccine effectively decreased amyloid-ß deposits, improved cognitive function and ameliorated mitochondrial dysfunction. These results indicate the potential of Aß3-10-KLH as a vaccine to treat AD.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/prevenção & controle , Vacinas contra Alzheimer/uso terapêutico , Precursor de Proteína beta-Amiloide/genética , Transtornos Cognitivos/prevenção & controle , Transtornos Cognitivos/psicologia , Doenças Mitocondriais/prevenção & controle , Presenilina-1/genética , Vacinas/uso terapêutico , Doença de Alzheimer/psicologia , Precursor de Proteína beta-Amiloide/imunologia , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Cognição , Humanos , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Doenças Mitocondriais/metabolismoRESUMO
Maternal antibodies (MAbs) protect against infections in immunologically-immature neonates. Maternally transferred immunity may also be harnessed to target diseases associated with endogenous protein misfolding and aggregation, such as Alzheimer's disease (AD) and AD-pathology in Down syndrome (DS). While familial early-onset AD (fEOAD) is associated with autosomal dominant mutations in the APP, PSEN1,2 genes, promoting cerebral Amyloid-ß (Aß) deposition, DS features a life-long overexpression of the APP and DYRK1A genes, leading to a cognitive decline mediated by Aß overproduction and tau hyperphosphorylation. Although no prenatal screening for fEOAD-related mutations is in clinical practice, DS can be diagnosed in utero. We hypothesized that anti-Aß MAbs might promote the removal of early Aß accumulation in the central nervous system of human APP-expressing mice. To this end, a DNA-vaccine expressing Aß1-11 was delivered to wild-type female mice, followed by mating with 5xFAD males, which exhibit early Aß plaque formation. MAbs reduce the offspring's cortical Aß levels 4 months after antibodies were undetectable, along with alleviating short-term memory deficits. MAbs elicit a long-term shift in microglial phenotype in a mechanism involving activation of the FcγR1/Syk/Cofilin pathway. These data suggest that maternal immunization can alleviate cognitive decline mediated by early Aß deposition, as occurs in EOAD and DS.
Assuntos
Doença de Alzheimer/enzimologia , Doença de Alzheimer/prevenção & controle , Vacinas contra Alzheimer/administração & dosagem , Peptídeos beta-Amiloides/metabolismo , Anticorpos/metabolismo , Encéfalo/enzimologia , Fragmentos de Peptídeos/administração & dosagem , Fagocitose , Receptores de IgG/metabolismo , Quinase Syk/metabolismo , Doença de Alzheimer/imunologia , Doença de Alzheimer/patologia , Vacinas contra Alzheimer/imunologia , Peptídeos beta-Amiloides/administração & dosagem , Peptídeos beta-Amiloides/imunologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Anticorpos/imunologia , Comportamento Animal , Encéfalo/imunologia , Encéfalo/patologia , Cognição , Modelos Animais de Doenças , Feminino , Imunização , Masculino , Memória , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/enzimologia , Microglia/imunologia , Microglia/patologia , Fragmentos de Peptídeos/imunologia , Fenótipo , Placa Amiloide , Transdução de Sinais , Vacinas de DNA/administração & dosagem , Vacinas de DNA/imunologiaRESUMO
ABT-736 is a humanized monoclonal antibody generated to target a specific conformation of the amyloid-beta (Aß) protein oligomer. Development of ABT-736 for Alzheimer's disease was discontinued due to severe adverse effects (AEs) observed in cynomolgus monkey toxicity studies. The acute nature of AEs observed only at the highest doses suggested potential binding of ABT-736 to an abundant plasma protein. Follow-up investigations indicated polyspecificity of ABT-736, including unintended high-affinity binding to monkey and human plasma protein platelet factor 4 (PF-4), known to be involved in heparin-induced thrombocytopenia (HIT) in humans. The chronic AEs observed at the lower doses after repeat administration in monkeys were consistent with HIT pathology. Screening for a backup antibody revealed that ABT-736 possessed additional unintended binding characteristics to other, unknown factors. A subsequently implemented screening funnel focused on nonspecific binding led to the identification of h4D10, a high-affinity Aß oligomer binding antibody that did not bind PF-4 or other unintended targets and had no AEs in vivo. This strengthened the hypothesis that ABT-736 toxicity was not Aß target-related, but instead was the consequence of polyspecificity including PF-4 binding, which likely mediated the acute and chronic AEs and the HIT-like pathology. In conclusion, thorough screening of antibody candidates for nonspecific interactions with unrelated molecules at early stages of discovery can eliminate candidates with polyspecificity and reduce potential for toxicity caused by off-target binding.
Assuntos
Vacinas contra Alzheimer/imunologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/toxicidade , Plaquetas/efeitos dos fármacos , Imunidade Heteróloga , Fator Plaquetário 4/antagonistas & inibidores , Púrpura Trombocitopênica Idiopática/induzido quimicamente , Vacinas contra Alzheimer/farmacocinética , Vacinas contra Alzheimer/toxicidade , Peptídeos beta-Amiloides/imunologia , Animais , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacocinética , Especificidade de Anticorpos , Plaquetas/imunologia , Plaquetas/metabolismo , Feminino , Humanos , Macaca fascicularis , Masculino , Camundongos Endogâmicos BALB C , Nível de Efeito Adverso não Observado , Ativação Plaquetária/efeitos dos fármacos , Fator Plaquetário 4/imunologia , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/imunologia , Medição de Risco , Fatores de Tempo , Testes de Toxicidade Aguda , Testes de Toxicidade CrônicaRESUMO
Amyloid-ß (Aß) and tau proteins currently represent the two most promising targets to treat Alzheimer's disease. The most extensively developed method to treat the pathologic forms of these proteins is through the administration of exogenous antibodies, or passive immunotherapy. In this review, we discuss the molecular-level strategies that researchers are using to design an effective therapeutic antibody, given the challenges in treating this disease. These challenges include selectively targeting a protein that has misfolded or is pathological rather than the more abundant, healthy protein, designing strategic constructs for immunizing an animal to raise an antibody that has the appropriate conformational selectivity to achieve this end, and clearing the pathological protein species before prion-like cell-to-cell spread of misfolded protein has irreparably damaged neurons, without invoking damaging inflammatory responses in the brain that naturally arise when the innate immune system is clearing foreign agents. The various solutions to these problems in current clinical trials will be discussed.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/imunologia , Anticorpos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Proteínas tau/imunologia , Vacinas contra Alzheimer/uso terapêutico , Anticorpos Monoclonais Humanizados , Desenho de Fármacos , Humanos , Imunização PassivaRESUMO
Immunotherapies targeting pathological tau have recently emerged as a promising approach for treatment of neurodegenerative disorders. We have previously showed that the mouse antibody DC8E8 discriminates between healthy and pathological tau, reduces tau pathology in murine tauopathy models and inhibits neuronal internalization of AD tau species in vitro.Here we show, that DC8E8 and antibodies elicited against the first-in-man tau vaccine, AADvac1, which is based on the DC8E8 epitope peptide, both promote uptake of pathological tau by mouse primary microglia. IgG1 and IgG4 isotypes of AX004, the humanized versions of DC8E8, accelerate tau uptake by human primary microglia isolated from post-mortem aged and diseased brains. This promoting activity requires the presence of the Fc-domain of the antibodies.The IgG1 isotype of AX004 showed greater ability to promote tau uptake compared to the IgG4 isotype, while none of the antibody-tau complexes provoked increased pro-inflammatory activity of microglia. Our data suggest that IgG1 has better suitability for therapeutic development.
Assuntos
Vacinas contra Alzheimer/imunologia , Anticorpos Monoclonais Humanizados/imunologia , Encefalite/imunologia , Microglia/imunologia , Proteínas tau/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos Monoclonais Humanizados/metabolismo , Transporte Biológico , Células Cultivadas , Encefalite/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Adulto Jovem , Proteínas tau/metabolismoRESUMO
BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the characteristics of this devastating disorder include the progressive and disabling deficits in the cognitive functions including reasoning, attention, judgment, comprehension, memory, and language. OBJECTIVE: In this article, we have focused on the recent progress that has been achieved in the development of an effective AD vaccine. SUMMARY: Currently, available treatment options of AD are limited to deliver short-term symptomatic relief only. A number of strategies targeting amyloid-beta (Aß) have been developed in order to treat or prevent AD. In order to exert an effective immune response, an AD vaccine should contain adjuvants that can induce an effective anti-inflammatory T helper 2 (Th2) immune response. AD vaccines should also possess the immunogens which have the capacity to stimulate a protective immune response against various cytotoxic Aß conformers. The induction of an effective vaccine's immune response would necessitate the parallel delivery of immunogen to dendritic cells (DCs) and their priming to stimulate a Th2-polarized response. The aforesaid immune response is likely to mediate the generation of neutralizing antibodies against the neurotoxic Aß oligomers (AßOs) and also anti-inflammatory cytokines, thus preventing the AD-related inflammation. CONCLUSION: Since there is an age-related decline in the immune functions, therefore vaccines are more likely to prevent AD instead of providing treatment. AD vaccines might be an effective and convenient approach to avoid the treatment-related huge expense.
Assuntos
Doença de Alzheimer/prevenção & controle , Doença de Alzheimer/terapia , Vacinas contra Alzheimer/imunologia , Imunoterapia , Doença de Alzheimer/imunologia , Vacinas contra Alzheimer/administração & dosagem , Animais , HumanosRESUMO
The DNA vaccine, AV-1959D, targeting N-terminal epitope of Aß peptide, has been proven immunogenic in mice, rabbits, and non-human primates, while its therapeutic efficacy has been shown in mouse models of Alzheimer's disease (AD). Here we report for the first time on IND-enabling biodistribution and safety/toxicology studies of cGMP-grade AV-1959D vaccine in the Tg2576 mouse model of AD. We also tested acute neuropathology safety profiles of AV-1959D in another AD disease model, Tg-SwDI mice with established vascular and parenchymal Aß pathology in a pre-clinical translational study. Biodistribution studies two days after the injection demonstrated high copy numbers of AV-1959D plasmid after single immunization of Tg2576 mice at the injection sites but not in the tissues of distant organs. Plasmids persisted at the injection sites of some mice 60 days after vaccination. In Tg2576 mice with established amyloid pathology, we did not observe short- or long-term toxicities after multiple immunizations with three doses of AV-1959D. Assessment of the repeated dose acute safety of AV-1959D in cerebral amyloid angiopathy (CAA) prone Tg-SwDI mice did not reveal any immunotherapy-induced vasogenic edema detected by magnetic resonance imaging (MRI) or increased microhemorrhages. Multiple immunizations of Tg-SwDI mice with AV-1959D did not induce T and B cell infiltration, glial activation, vascular deposition of Aß, or neuronal degeneration (necrosis and apoptosis) greater than that in the control group determined by immunohistochemistry of brain tissues. Taken together, the safety data from two different mouse models of AD substantiate a favorable safety profile of the cGMP grade AV-1959D vaccine supporting its progression to first-in-human clinical trials.
Assuntos
Vacinas contra Alzheimer/imunologia , Vacinas de DNA/imunologia , Adjuvantes Imunológicos , Doença de Alzheimer/imunologia , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/metabolismo , Animais , Formação de Anticorpos , Angiopatia Amiloide Cerebral/imunologia , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Fragmentos de Peptídeos/metabolismoRESUMO
BACKGROUND: Pyroglutamate-3 Aß (pGlu-3 Aß) is an N-terminally truncated and post-translationally modified Aß species found in Alzheimer's disease (AD) brain. Its increased peptide aggregation propensity and toxicity make it an attractive emerging treatment strategy for AD. We address the question of how the effector function of an anti-pGlu-3 Aß antibody influences the efficacy of immunotherapy in mouse models with AD-like pathology. METHODS: We compared two different immunoglobulin (Ig) isotypes of the same murine anti-pGlu-3 Aß mAb (07/1 IgG1 and 07/2a IgG2a) and a general N-terminal Aß mAb (3A1 IgG1) for their ability to clear Aß and protect cognition in a therapeutic passive immunotherapy study in aged, plaque-rich APPSWE/PS1ΔE9 transgenic (Tg) mice. We also compared the ability of these antibodies and a CDC-mutant form of 07/2a (07/2a-k), engineered to avoid complement activation, to clear Aß in an ex vivo phagocytosis assay and following treatment in APPSLxhQC double Tg mice, and to activate microglia using longitudinal microPET imaging with TSPO-specific 18F-GE180 tracer following a single bolus antibody injection in young and old Tg mice. RESULTS: We demonstrated significant cognitive improvement, better plaque clearance, and more plaque-associated microglia in the absence of microhemorrhage in aged APPSWE/PS1ΔE9 Tg mice treated with 07/2a, but not 07/1 or 3A1, compared to PBS in our first in vivo study. All mAbs cleared plaques in an ex vivo assay, although 07/2a promoted the highest phagocytic activity. Compared with 07/2a, 07/2a-k showed slightly reduced affinity to Fcγ receptors CD32 and CD64, although the two antibodies had similar binding affinities to pGlu-3 Aß. Treatment of APPSLxhQC mice with 07/2a and 07/2a-k mAbs in our second in vivo study showed significant plaque-lowering with both mAbs. Longitudinal 18F-GE180 microPET imaging revealed different temporal patterns of microglial activation for 3A1, 07/1, and 07/2a mAbs and no difference between 07/2a-k and PBS-treated Tg mice. CONCLUSION: Our results suggest that attenuation of behavioral deficits and clearance of amyloid is associated with strong effector function of the anti-pGlu-3 Aß mAb in a therapeutic treatment paradigm. We present evidence that antibody engineering to reduce CDC-mediated complement binding facilitates phagocytosis of plaques without inducing neuroinflammation in vivo. Hence, the results provide implications for tailoring effector function of humanized antibodies for clinical development.
Assuntos
Doença de Alzheimer , Vacinas contra Alzheimer/farmacologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Anticorpos Monoclonais/farmacologia , Neuroglia/efeitos dos fármacos , Animais , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Imunização Passiva/métodos , Imunoglobulina G , Camundongos , Camundongos Transgênicos , Processamento de Proteína Pós-Traducional , Ácido Pirrolidonocarboxílico/metabolismoRESUMO
Quantum mechanics-based design of useful catalytic antibodies (catabodies) failed because of the uncertain structure of the dynamic catalyst-substrate complex. The Catabody Platform emerged from discovery of beneficial germline gene catabodies that hydrolyzed self-proteins by transient covalent pairing of the strong catabody nucleophile with a weak target protein electrophile. Catabodies have evolved by Darwinian natural selection for protection against misfolded self-proteins that threatened survival by causing amyloid disease. Ancient antibody scaffolds upregulate the catalytic activity of the antibody variable (V) domains. Healthy humans universally produce beneficial catabodies specific for at least 3 misfolded self-proteins, transthyretin, amyloid ß peptide and tau protein. Catabody are superior to ordinary antibodies because of catalyst reuse for thousands of target destruction cycles with little or no risk of causing inflammation, a must for non-toxic removal of abundant targets such as amyloids. Library mining with electrophilic target analogs (ETAs) isolates therapy-grade catabodies (fast, specific). Ex vivo- and in vivo-verified catabodies specific for the misfolded protein are available to dissolve brain, cardiac and vertebral amyloids. Immunization with ETAs overcomes important ordinary vaccine limitations (no catabody induction, poor immunogenicity of key target epitopes). We conceive electrophilic longevity vaccines that can induce catabody synthesis for long-lasting protection against amyloid disease.
Assuntos
Envelhecimento/fisiologia , Amiloidose , Anticorpos Catalíticos/fisiologia , Homeostase/fisiologia , Vacinas contra Alzheimer/farmacologia , Peptídeos beta-Amiloides/metabolismo , Amiloidose/imunologia , Amiloidose/metabolismo , Amiloidose/prevenção & controle , Humanos , Imunogenicidade da Vacina , Dobramento de ProteínaRESUMO
Abnormal tau hyperphosphorylation and its aggregation into neurofibrillary tangles are a hallmark of tauopathies, neurodegenerative disorders that include Alzheimer's disease (AD). Active and passive Tau-immunotherapy has been proposed as a therapeutic approach to AD with mixed results. One of the limitations of active immunotherapy may be associated with the mediocre immunogenicity of vaccines that are not inducing therapeutically potent titers of antibodies. The aim of this study was to test the efficacy of an anti-tau vaccine, AV-1980R/A composed of N terminal peptide of this molecule fused with an immunogenic MultiTEP platform and formulated in a strong adjuvant, AdvaxCpG in a Tg4510 mouse model of tauopathy. Experimental mice were immunized with AV-1980R/A and a control group of mice were injected with adjuvant only. Nontransgenic and tetracycline transactivator (tTA) transgenic littermates were included as baseline controls to contrast with the tau phenotype. Active immunization with AV-1980R/A induced very strong anti-tau humoral immune responses in both nontransgenic and transgenic mice with evidence of IgG in brains of AV-1980R/A vaccinated mice. These experimental animals displayed an improvement in short-term memory during a novel object recognition test. However, impairments in other behavioral tasks were not prevented by AV-1980R/A vaccinations. At the same time, high titers of anti-tau antibodies reduced hyperphosphorylated pSer396 tau but did not lower the level of other phosphorylated tau species in the brains of AV-1980R/A vaccinated mice. These data indicate that active immunotherapy with an N-terminal Tau epitope was only partially effective in improving cognition and reducing pathology in the stringent Tg4510 mouse model of tauopathy.
Assuntos
Vacinas contra Alzheimer , Imunogenicidade da Vacina/imunologia , Tauopatias , Vacinação , Proteínas tau/imunologia , Animais , Formação de Anticorpos , Modelos Animais de Doenças , Epitopos/imunologia , Memória , Camundongos , Camundongos TransgênicosRESUMO
Vaccination traditionally has targeted infectious agents and thus has not heretofore been used to prevent neurodegenerative illness. However, amyloid ß (Aß) or tau, which can act like infectious proteins, or prions, might induce Alzheimer's disease (AD). Furthermore, evidence suggests that traditional infectious agents, including certain viruses and bacteria, may trigger AD. It is therefore worth exploring whether removing such targets could prevent AD. Although failing to treat AD patients who already display cognitive impairment, Aß monoclonal antibodies are being tested in pre-symptomatic, at-risk individuals to prevent dementia. These antibodies might become the first AD therapeutics. However, their high cost will keep them out of the arms of the vast majority of patients, who increasingly live in developing countries. Because vaccines produce antibodies internally at much lower cost, vaccination might be the most promising approach to reducing the global burden of dementia.
Assuntos
Doença de Alzheimer , Vacinas contra Alzheimer , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides , Anticorpos Monoclonais , HumanosRESUMO
Introduction: Alzheimer's disease (AD) vaccination is one of the last therapeutic options after two decades of stagnation in terms of drug development. About 140 (85%) immunization procedures against Aß deposition and 25 (15%) against Tau have been reported, but no Food and Drug Administration approval of any AD vaccine has been achieved. This might be attributed to deficient pathogenic targets, inappropriate models, defective immunotherapeutic procedures, and inadequate clinical trial design.Areas covered: The issues covered include the following: AD pathogenic mechanisms, rationale for active and passive immunization, vaccine targets, anti-Aß/Tau vaccines, vaccine technologies, animal models, and clinical trials.Expert opinion: A vaccine against AD is technically feasible; however, important methodological aspects should be changed for a tentative clinical success, including (i) the development of multitarget AD immunotherapies; (ii) the optimization of antibody titers and epitopes; (iii) the pharmacogenetic/pharmacoepigenetic validation of the immunization procedure; (iv) the prophylactic treatment of genetically stratified patients at a pre-symptomatic stage; and (v) the definition of primary endpoints in prevention, based on objective/multifactorial biomarkers. Even with exquisite protocols, a successful vaccine would be potentially useful in at most 20-30% of defined cases, according to the genetic, epigenetic, and pharmacogenetic background of AD patients.
Assuntos
Doença de Alzheimer/terapia , Vacinas contra Alzheimer/imunologia , Vacinas contra Alzheimer/uso terapêutico , Humanos , Imunoterapia , Proteínas tauRESUMO
BACKGROUND: Alzheimer disease (AD) is characterized by the accumulation of beta-amyloid (Aß) plaques and neurofibrillary tangles composed of hyperphosphorylated tau, which together lead to neurodegeneration and cognitive decline. Current therapeutic approaches have primarily aimed to reduce pathological aggregates of either Aß or tau, yet phase 3 clinical trials of these approaches have thus far failed to delay disease progression in humans. Strong preclinical evidence indicates that these two abnormally aggregated proteins interact synergistically to drive downstream neurodegeneration. Therefore, combinatorial therapies that concurrently target both Aß and tau might be needed for effective disease modification. METHODS: A combinatorial vaccination approach was designed to concurrently target both Aß and tau pathologies. Tau22/5xFAD (T5x) bigenic mice that develop both pathological Aß and tau aggregates were injected intramuscularly with a mixture of two MultiTEP epitope vaccines: AV-1959R and AV-1980R, targeting Aß and tau, respectively, and formulated in AdvaxCpG, a potent polysaccharide adjuvant. Antibody responses of vaccinated animals were measured by ELISA, and neuropathological changes were determined in brain homogenates of vaccinated and control mice using ELISA and Meso Scale Discovery (MSD) multiplex assays. RESULTS: T5x mice immunized with a mixture of Aß- and tau-targeting vaccines generated high Aß- and tau-specific antibody titers that recognized senile plaques and neurofibrillary tangles/neuropil threads in human AD brain sections. Production of these antibodies in turn led to significant reductions in the levels of soluble and insoluble total tau, and hyperphosphorylated tau as well as insoluble Aß42, within the brains of bigenic T5x mice. CONCLUSIONS: AV-1959R and AV-1980R formulated with AdvaxCpG adjuvant are immunogenic and therapeutically potent vaccines that in combination can effectively reduce both of the hallmark pathologies of AD in bigenic mice. Taken together, these findings warrant further development of this vaccine technology for ultimate testing in human AD.
Assuntos
Doença de Alzheimer/terapia , Vacinas contra Alzheimer , Peptídeos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologiaRESUMO
Alzheimer disease (AD) is a heterogeneous disease with a complex pathobiology. The presence of extracellular ß-amyloid deposition as neuritic plaques and intracellular accumulation of hyperphosphorylated tau as neurofibrillary tangles remains the primary neuropathologic criteria for AD diagnosis. However, a number of recent fundamental discoveries highlight important pathological roles for other critical cellular and molecular processes. Despite this, no disease-modifying treatment currently exists, and numerous phase 3 clinical trials have failed to demonstrate benefits. Here, we review recent advances in our understanding of AD pathobiology and discuss current treatment strategies, highlighting recent clinical trials and opportunities for developing future disease-modifying therapies.