Abstract
Amyloidosis is a term referring to a group of various protein-misfolding diseases wherein normally soluble proteins form aggregates as insoluble amyloid fibrils. How, or whether, amyloid fibrils contribute to tissue damage in amyloidosis has been the topic of debate. In vitro studies have demonstrated the appearance of small globular oligomeric species during the incubation of amyloid beta peptide (Aβ). Nerve biopsy specimens from patients with systemic amyloidosis have suggested that globular structures similar to Aβ oligomers were generated from amorphous electron-dense materials and later developed into mature amyloid fibrils. Schwann cells adjacent to amyloid fibrils become atrophic and degenerative, suggesting that the direct tissue damage induced by amyloid fibrils plays an important role in systemic amyloidosis. In contrast, there is increasing evidence that oligomers, rather than amyloid fibrils, are responsible for cell death in neurodegenerative diseases, particularly Alzheimer’s disease. Disease-modifying therapies based on the pathophysiology of amyloidosis have now become available. Aducanumab, a human monoclonal antibody against the aggregated form of Aβ, was recently approved for Alzheimer’s disease, and other monoclonal antibodies, including gantenerumab, solanezumab, and lecanemab, could also be up for approval. As many other agents for amyloidosis will be developed in the future, studies to develop sensitive clinical scales for identifying improvement and markers that can act as surrogates for clinical scales should be conducted.
Highlights
Accepted: 20 August 2021Amyloidosis is a term referring to a group of toxic gain-of-function protein-misfolding diseases wherein normally soluble proteins aggregate in extracellular spaces as insoluble amyloid fibrils with a beta (β)-sheet structure [1,2]
We describe the pathophysiological aspects of amyloidosis, focusing on the prefibrillar states of amyloidogenic proteins and their evolution to amyloid fibrils
Observations of nerve biopsy specimens obtained from patients with hereditary ATTR (ATTRv; v for variant) amyloidosis using electron microscopy suggest that globular structures of similar diameter to amyloid β peptide (Aβ) intermediates were generated from amorphous electron-dense materials [7,17]
Summary
Amyloidosis is a term referring to a group of toxic gain-of-function protein-misfolding diseases wherein normally soluble proteins aggregate in extracellular spaces as insoluble amyloid fibrils with a beta (β)-sheet structure [1,2]. Amyloid fibril formation or released from amyloid fibril aggregates are considered as causes of cellular dysfunction and degeneration [22,23,24,25] In support of this view, the severity of cognitive decline in patients with Alzheimer’s disease does not correlate with amyloid plaque formation, suggesting that pre-amyloid aggregates are the cause of disease [26,27]. From this standpoint, clarifying the significance of amyloidogenic protein oligomers is important to understanding the pathophysiology and establishing therapeutic strategies for amyloidosis. We describe the pathophysiological aspects of amyloidosis, focusing on the prefibrillar states of amyloidogenic proteins and their evolution to amyloid fibrils
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