1,721,216 research outputs found
Proteinopathies, a core concept for understanding and ultimately treating degenerative disorders?
No full textThe current review covers proteinopathies an umbrella term for neurodegenerative disorders that are characterized by the accumulation of specific proteins within neurons or in the brain parenchyma. Most prevalent examples for typical proteinopathies are Alzheimer's disease and Parkinson's disease. In healthy brain, these proteins are unstructured as a monomer, serving most likely as the physiological form. In a disease condition, the unstructured proteins experience a conformational change leading to small oligomers that eventually will aggregate into higher order structures. Prion disease is an exception within the family of proteinopathies as the aggregated prion protein is highly infectious and can self-aggregate and propagate. Recent reports might implicate a prion-like spread of misfolded proteins in Alzheimer's and Parkinson's disease; however there are evident differences in comparison to prion diseases. As proteinopathies are caused by the aggregation of disease-typical proteins with an ordered structure, active and passive immunization protocols have been used to expose model systems to therapeutic antibodies that bind to the aggregates thereby inhibiting the prolongation into higher ordered fibrils or dissolving the existing fibrillar structure. While most of the immunization treatments have been only carried out in preclinical model systems overexpressing the disease-relevant aggregating protein, other approaches are already in clinical testing. Taking the core concept of proteinopathies with conformationally altered protein aggregates into account, immunization appears to be a very promising therapeutic option for neurodegenerative disorders. (C) 2013 Elsevier B.V. and ECNR All rights reserved
N-Truncated Aβ Starting at Position Four-Biochemical Features, Preclinical Models, and Potential as Drug Target in Alzheimer's Disease
No full textThe discussion of whether amyloid plaque Aβ is a valid drug target to fight Alzheimer's disease (AD) has been a matter of scientific dispute for decades. This question can only be settled by successful clinical trials and the approval of disease-modifying drugs. However, many clinical trials with antibodies against different regions of the amyloid Aβ peptide have been discontinued, as they did not meet the clinical endpoints required. Recently, passive immunization of AD patients with Donanemab, an antibody directed against the N-terminus of pyroglutamate Aβ, showed beneficial effects in a phase II trial, supporting the concept that N-truncated Aβ is a relevant target for AD therapy. There is long-standing evidence that N-truncated Aβ variants are the main variants found in amyloid plaques besides full-length Aβ1-42, t, therefore their role in triggering AD pathology and as targets for drug development are of interest. While the contribution of pyroglutamate Aβ3-42 to AD pathology has been well studied in the past, the potential role of Aβ4-42 has been largely neglected. The present review will therefore focus on Aβ4-42 as a possible drug target based on human and mouse pathology, in vitro and in vivo toxicity, and anti-Aβ4-X therapeutic effects in preclinical models
The modified amyloid hypothesis of Alzheimer dementia - intraneuronal Abeta induces neurodegeneration
No full textThe present short review recapitulates the molecular pathology of Alzheimer's disease and discusses the most important animal models and current treatment strategies. The currently approved and only mildly efficient drugs treat only symptoms. Genetical, neuropathological and biochemical data support the importance of the amyloid hypothesis of Alzheimer's disease, which is at the moment the most influential hypothesis. The resulting research approaches have disease-modifying potential. At the basis of the amlyloid hypothesis many treatment strategies have been performed, which were markedly successful in preclinical animal models. However, the treatment success in Alzheimer patients is unfortunately still lacking. This could be due to the used animal models showing mostly only marginal behavioural deficits and no Alzheimer-like nerve cell loss, although they all developed a more or less pronounced plaque load. We know however today, that Alzheimer plaques are not mainly responsible for the cell loss. Therefore novel animal models have been developed that show early intraneuronal A beta accumulation, massive neuron loss and robust behavioural deficits. A successful treatment of an animal model with such a phenotype would be very likely better suited to be transferred into the clinic. The final validation or falsification of distinct Alzheimer hypotheses and the resulting treatment strategies will be obtained however only after clinical proof
Intraneuronal A beta accumulation and neurodegeneration: Lessons from transgenic models
No full textAims: In the present review we summarize current knowledge on the concept of intraneuronal A beta as a determinant for neuron loss and other pathological alterations in transgenic models for Alzheimer disease. Main methods: We discuss the use of transgenic mouse and non-vertebrate transgenic models accumulating intracellular A beta peptides and their impact on the ongoing discussion. Key findings: Intraneuronal A beta accumulation in transgenic models is intimately linked to pathological alterations including neuron loss. One of the technical caveats for visualizing intraneuronal A beta is the antibody used to unequivocally demonstrate its presence. Very often antibodies were used that recognize both A beta and APP, leading to false positive results due to misinterpretation. Significance: Whereas a clear relationship between intraneuronal A beta accumulation and neuron loss is evident in transgenic mouse models it remains an unresolved issue whether the concept of intraneuronal A beta can be integrated into the human pathology as well. (C) 2012 Elsevier Inc. All rights reserved
The modified amyloid hypothesis of Alzheimer dementia - intraneuronal Abeta induces neurodegeneration
No full textThe present short review recapitulates the molecular pathology of Alzheimer's disease and discusses the most important animal models and current treatment strategies. The currently approved and only mildly efficient drugs treat only symptoms. Genetical, neuropathological and biochemical data support the importance of the amyloid hypothesis of Alzheimer's disease, which is at the moment the most influential hypothesis. The resulting research approaches have disease-modifying potential. At the basis of the amlyloid hypothesis many treatment strategies have been performed, which were markedly successful in preclinical animal models. However, the treatment success in Alzheimer patients is unfortunately still lacking. This could be due to the used animal models showing mostly only marginal behavioural deficits and no Alzheimer-like nerve cell loss, although they all developed a more or less pronounced plaque load. We know however today, that Alzheimer plaques are not mainly responsible for the cell loss. Therefore novel animal models have been developed that show early intraneuronal A beta accumulation, massive neuron loss and robust behavioural deficits. A successful treatment of an animal model with such a phenotype would be very likely better suited to be transferred into the clinic. The final validation or falsification of distinct Alzheimer hypotheses and the resulting treatment strategies will be obtained however only after clinical proof
Alzheimer's disease Molecular pathology, animal models, and current treatment
No full textThe currently approved but only mildly efficient drugs against Alzheimer's disease treat merely the symptoms. Genetic, neuropathological, and biochemical data support the importance of the amyloid hypothesis of Alzheimer's disease, at the moment the most influential hypothesis. Many treatment strategies have been performed based on this hypothesis and were markedly successful in preclinical animal models. Unfortunately the treatment is still unsuccessful in humans. This could be due to the animal models showing marginal behavioural deficits but no Alzheimer-like nerve cell loss, although they all developed a more or less pronounced plaque load. Today we know however that Alzheimer plaques are not mainly responsible for the cell loss. Therefore novel animal models have been developed that show age-dependent axonal degeneration, massive neuronal loss, and robust behavioural deficits. Successful treatment of an animal model with such robust deficits would be very likely better suited to transferral into the clinic. The final validation or disproof of individual Alzheimer hypotheses and their resulting treatment strategies can however be obtained only after clinical proof
New insights into Alzheimer’s disease: ‘modeling neurodegeneration - causes and consequences’
No full textIntracellular accumulation of amyloid-beta - a predictor for synaptic dysfunction and neuron loss in Alzheimer's disease
No full textDespite of long-standing evidence that beta-amyloid (Aβ) peptides have detrimental effects on synaptic function, the relationship between Aβ, synaptic and neuron loss is largely unclear. During the last years there is growing evidence that early intraneuronal accumulation of Aβ peptides is one of the key events leading to synaptic and neuronal dysfunction. Many studies have been carried out using transgenic mouse models of Alzheimer’s disease (AD) which have been proven to be valuable model system in modern AD research. The present review discusses the impact of intraneuronal Aβ accumulation on synaptic impairment and neuron loss and provides an overview of currently available AD mouse models showing these pathological alterations
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