O2‐05‐03: Immunotherapy targeting abnormal protein conformation

Goñi

2015

Neuron

Self Cite

259

220

Alzheimer’s disease (AD) is the most prevalent form of dementia worldwide and is an emerging global epidemic. It is characterized by an imbalance between production and clearance of amyloid β (Aβ) and tau proteins. Oligomeric forms of Aβ and tau are believed to be the most toxic. Dramatic results from AD animal models showed great promise for active and passive immune therapies targeting Aβ. However, there is very limited evidence in human studies of clinical benefits from these approaches. Immunotherapies targeting only tau pathology have had some success but are limited so far to mouse models. The majority of current methods is based on immunological targeting of a self-protein; hence, benefits needed to be balanced against risks of stimulating excessive auto-immune toxic inflammation. For greater efficacy the next generation of vaccines will need to focus more on concurrently targeting all the intermediate toxic conformers of oligomeric Aβ and tau species.

Section: Targeting Abnormal Protein Conformation Rather Than Aβ or Tamentioning

confidence: 99%

Immunotherapeutic Approaches for Alzheimer’s Disease

Goñi

2015

Neuron

Self Cite

259

220

“…Targeting only the oligomeric forms of Aβ or tau would also avoid the potential of interfering with the normal physiological functions of these proteins. A novel immunotherapeutic approach is to target the shared abnormal β-sheet conformation of amyloid proteins using conformationally specific antibodies or active immunization that favors such an anti-conformational response [120,121,125]. Such an approach has the advantage that both Aβ and tau related pathologies would be addressed concurrently.…”

Section: Targeting Abnormal Protein Conformation Instead Of Aiming Atmentioning

confidence: 99%

Immunotherapy for Alzheimer's disease

Biochemical Pharmacology

Goñi

2014

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Alzheimer's disease (AD) is the most common cause of dementia worldwide. In AD the normal soluble amyloid β (sAβ) peptide is converted into oligomeric/fibrillar Aβ. The oligomeric forms of Aβ are thought to be the most toxic, while fibrillar Aβ becomes deposited as amyloid plaques and congophilic angiopathy, which serve as neuropathological markers of the disease. In addition the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is a critical part of the pathology. Numerous therapeutic interventions are under investigation to prevent and treat AD. Among the more exciting and advanced of these approaches is vaccination. Active and passive Immunotherapy targeting only Aβ has been successful in many AD model animal trials; however, the more limited human data has shown much less benefit so far, with encephalitis occurring in a minority of patients treated with active immunization and vasogenic edema or amyloid-related imaging abnormalities (ARIA) being a complication in some passive immunization trials. Therapeutic intervention targeting only tau has been tested only in mouse models; and no approaches targeting both pathologies concurrently has been attempted, until very recently. The immune approaches tried so far were targeting a self-protein, albeit in an abnormal conformation; however, effective enhanced clearance of the disease associated conformer has to be balanced with the potential risk of stimulating excessive toxic inflammation. The design of future more effective immunomodulatory approaches will need to target all aspects of AD pathology, as well as specifically targeting pathological oligomeric conformers, without the use of any self-antigen.

“…Targeting only oligomeric Aβ or tau would avoid potential interference with these physiological functions. A novel immunotherapeutic approach is to target the shared abnormal β-sheet conformation of amyloid proteins using conformationally specific antibodies or active immunization that favors such a conformational response [223,224,231,232]. Such an approach has the advantage that both Aβ and tau-related pathologies would be addressed concurrently.…”

Section: Immunization Targeting Aβ and Tau Oligomersmentioning

confidence: 99%

Murine models of Alzheimer's disease and their use in developing immunotherapies

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

Sigurdsson

2010

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Alzheimer's disease (AD) is one of the categories of neurodegenerative diseases characterized by a conformational change of a normal protein into a pathological conformer with a high β-sheet content that renders it resistant to degradation and neurotoxic. In AD, the normal soluble amyloid β (sAβ) peptide is converted into oligomeric/fibrillar Aβ. The oligomeric forms of Aβ are thought to be the most toxic, while fibrillar Aβ becomes deposited as amyloid plaques and congophilic angiopathy, which both serve as neuropathological markers of the disease. An additional important feature of AD is the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles. Many therapeutic interventions are under investigation to prevent and treat AD. The testing of these diverse approaches to ameliorate AD pathology has been made possible by the existence of numerous transgenic mouse models which each mirror specific aspects of AD pathology. None of the current murine models is a perfect match of the human disease. Perhaps the most exciting of the therapeutic approaches being developed is immunomodulation targeting the aggregating proteins, Aβ and tau. This type of AD therapy is currently being assessed in many transgenic mouse models, and promising findings have led to clinical trials. However, there is a discrepancy between results in murine models and ongoing clinical trials, which highlight the limitations of these models and also of our understanding of the underlying etiology and pathogenesis of AD. Because of these uncertainties, Tg models for AD are continuously being refined with the aim to better understand the disease and to enhance the predictive validity of potential treatments such as immunotherapies.