Diverse Structural Conversion and Aggregation Pathways of Alzheimerʼs Amyloid-β (1–40)

Abstract

Complex amyloid aggregation of amyloid-β (1–40) (Aβ1–40) in terms of monomer structures has not been fully understood. Herein, we report the microscopic mechanism and pathways of Aβ1–40 aggregation with macroscopic viewpoints through tuning its initial structure and solubility. Partial helical structures of Aβ1–40 induced by low solvent polarity accelerated cytotoxic Aβ1–40 amyloid fibrillation, while predominantly helical folds did not aggregate. Changes in the solvent polarity caused a rapid formation of β-structure-rich protofibrils or oligomers via aggregation-prone helical structures. Modulation of the pH and salt concentration transformed oligomers to protofibrils, which proceeded to amyloid formation. We reveal diverse molecular mechanisms underlying Aβ1–40 aggregation with conceptual energy diagrams and propose that aggregation-prone partial helical structures are key to inducing amyloidogenesis. We demonstrate that context-dependent protein aggregation is comprehensively understood using the macroscopic phase diagram, which provides general insights into differentiation of amyloid formation and phase separation from unfolded and folded structures.

Light‐Induced Chiral Iron Copper Selenide Nanoparticles Prevent β‐Amyloidopathy In Vivo

“…The misfolding and abnormal assembly of cerebral proteins into insoluble amyloid plaques consistently results in physiological dysfunction and the progressive loss of cognitive ability . In particular, Aβ fibrils can contain many copies of misfolded protein monomers and are a well‐known hallmark of Alzheimer's disease (AD) .…”

“…[17,20,21] Them isfolding and abnormal assembly of cerebral proteins into insoluble amyloid plaques consistently results in physiological dysfunction and the progressive loss of cognitive ability. [22][23][24][25] In particular,A b fibrils can contain many copies of misfolded protein monomers and are aw ellknown hallmark of Alzheimersd isease (AD). [26][27][28][29][30][31] Consequently,t he elimination or inhibition of Ab aggregation is considered to be apromising therapeutic option for AD.…”

Mixing Aβ(1–40) and Aβ(1–42) peptides generates unique amyloid fibrils

“…The formation of mixed intermediate species has been proposed, 17 and can be considered the result of the diverse conversion and aggregation pathways of these peptides. 15,18,19 However, it is widely believed that Ab and Ab(1-40) do not co-fibrillize. 17 Whether the two alloforms interplay or act separately instead is an important question, as this has implications for the propagation of fibrillar seeds in the brain.…”

Insights into Characterization Methods and Biomedical Applications of Nanoparticle–Protein Corona

“… ( a ) Schematic representation of the protein fibrillation process. Reprinted with permission from [ 180 ]. Copyright (2019) American Chemical Society.…”