Significance of Oligomeric and Fibrillar Species in Amyloidosis: Insights into Pathophysiology and Treatment

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.

Oxidative Stress and Beta Amyloid in Alzheimer’s Disease. Which Comes First: The Chicken or the Egg?

“…The term soluble Aβ is a working definition, which combines all forms of Aβ derived from physiological brain extracts that remain in aqueous solution after high-speed centrifugation [ 33 ]. Soluble oligomers released by cells have been shown to cause neuronal dysfunction in vivo as well as synaptic loss and cognitive impairment [ 34 , 35 , 36 , 37 , 38 , 39 , 40 ].…”

“…Experimentally, soluble Aβ oligomers have been found to selectively block hippocampal long-term potentiation (LTP), widely believed to underlie learning and memory [ 35 , 36 ]. Importantly, active and passive Aβ immunotherapies have been shown to protect against the neuropathological and cognitive deficits observed in APP transgenic models of AD and in AD patients [ 37 , 38 ].…”

Dissecting the Crosstalk between Endothelial Mitochondrial Damage, Vascular Inflammation, and Neurodegeneration in Cerebral Amyloid Angiopathy and Alzheimer’s Disease

“…In 2021, after nearly twenty years of attempts to develop new therapeutic strategies, aducanumab, a human monoclonal antibody that selectively targets aggregated amyloid-β (Aβ), has been approved by the FDA (through the accelerated approval pathway) for treatment of patients with AD [ 2 ]. However, the therapeutic effectiveness of aducanumab is still debated by many research groups [ 2 , 3 , 4 ]. The high prevalence of AD among aged individuals and lack of effective therapy denotes the importance of developing new therapeutics, and to do so we need to have a better understanding of the complexity of the disease.…”

Neuroprotective Activity of Melittin—The Main Component of Bee Venom—Against Oxidative Stress Induced by Aβ25–35 in In Vitro and In Vivo Models

“…Regarding the establishment of a neurodegenerative model for this study: Aβ aggregated species in neurodegenerative brains is considered a major cause of the onset of cognitive dysfunction disease because of its ability to alter intercellular redox balance [ 7 , 12 , 13 ]. Among Aβ variances, the Aβ 25 –35 fragment is the shortest segment that was proven to have similar oxidative neurotoxicity output compared with the full-length Aβ 1 –42 [ 14 ].…”