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Abstract
Several neurodegenerative diseases, including Alzheimers, Parkinsons, Huntingtons and prion diseases, are characterized pathognomonically by the presence of intra- and/or extracellular lesions containing proteinaceous aggregates, and by extensive neuronal loss in selective brain regions. Related non-neuropathic systemic diseases, e.g., lightchain and senile systemic amyloidoses, and other organ-specific diseases, such as dialysis-related amyloidosis and type-2 diabetes mellitus, also are characterized by deposition of aberrantly folded, insoluble proteins. It is debated whether the hallmark pathologic lesions are causative. Substantial evidence suggests that these aggregates are the end state of aberrant protein folding whereas the actual culprits likely are transient, pre-fibrillar assemblies preceding the aggregates. In the context of neurodegenerative amyloidoses, the proteinaceous aggregates may eventuate as potentially neuroprotective sinks for the neurotoxic, oligomeric protein assemblies. The pre-fibrillar, oligomeric assemblies are believed to initiate the pathogenic mechanisms that lead to synaptic dysfunction, neuronal loss, and disease-specific regional brain atrophy. The amyloid β-protein (Aβ), which is believed to cause Alzheimers disease (AD), is considered an archetypal amyloidogenic protein. Intense studies have led to nominal, functional, and structural descriptions of oligomeric Aβ assemblies. However, the dynamic and metastable nature of Aβ oligomers renders their study difficult. Different results generated using different methodologies under different experimental settings further complicate this complex area of research and identification of the exact pathogenic assemblies in vivo seems daunting. Here we review structural, functional, and biological experiments used to produce and study pre-fibrillar Aβ assemblies, and highlight similar studies of proteins involved in related diseases. We discuss challenges that contemporary researchers are facing and future research prospects in this demanding yet highly important field.
Keywords: Amyloid, neurodegeneration, Alzheimer's disease, amyloid β-protein, protein misfolding, pre-fibrillar assemblies, oligomers, toxicity
Current Alzheimer Research
Title: Structure – Function Relationships of Pre-Fibrillar Protein Assemblies in Alzheimers Disease and Related Disorders
Volume: 5 Issue: 3
Author(s): F. Rahimi, A. Shanmugam and G. Bitan
Affiliation:
Keywords: Amyloid, neurodegeneration, Alzheimer's disease, amyloid β-protein, protein misfolding, pre-fibrillar assemblies, oligomers, toxicity
Abstract: Several neurodegenerative diseases, including Alzheimers, Parkinsons, Huntingtons and prion diseases, are characterized pathognomonically by the presence of intra- and/or extracellular lesions containing proteinaceous aggregates, and by extensive neuronal loss in selective brain regions. Related non-neuropathic systemic diseases, e.g., lightchain and senile systemic amyloidoses, and other organ-specific diseases, such as dialysis-related amyloidosis and type-2 diabetes mellitus, also are characterized by deposition of aberrantly folded, insoluble proteins. It is debated whether the hallmark pathologic lesions are causative. Substantial evidence suggests that these aggregates are the end state of aberrant protein folding whereas the actual culprits likely are transient, pre-fibrillar assemblies preceding the aggregates. In the context of neurodegenerative amyloidoses, the proteinaceous aggregates may eventuate as potentially neuroprotective sinks for the neurotoxic, oligomeric protein assemblies. The pre-fibrillar, oligomeric assemblies are believed to initiate the pathogenic mechanisms that lead to synaptic dysfunction, neuronal loss, and disease-specific regional brain atrophy. The amyloid β-protein (Aβ), which is believed to cause Alzheimers disease (AD), is considered an archetypal amyloidogenic protein. Intense studies have led to nominal, functional, and structural descriptions of oligomeric Aβ assemblies. However, the dynamic and metastable nature of Aβ oligomers renders their study difficult. Different results generated using different methodologies under different experimental settings further complicate this complex area of research and identification of the exact pathogenic assemblies in vivo seems daunting. Here we review structural, functional, and biological experiments used to produce and study pre-fibrillar Aβ assemblies, and highlight similar studies of proteins involved in related diseases. We discuss challenges that contemporary researchers are facing and future research prospects in this demanding yet highly important field.
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Cite this article as:
Rahimi F., Shanmugam A. and Bitan G., Structure – Function Relationships of Pre-Fibrillar Protein Assemblies in Alzheimers Disease and Related Disorders, Current Alzheimer Research 2008; 5 (3) . https://dx.doi.org/10.2174/156720508784533358
DOI https://dx.doi.org/10.2174/156720508784533358 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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