Cascade autohydrolysis of Alzheimer's Aβ peptides

Abstract

Protein/peptide self-assembly into amyloid structures associates with major neurodegenerative disorders such as Alzheimer’s disease (AD). Soluble assemblies (oligomers) of the Aβ peptide and their aggregates are perceived as neurotoxic species...

Hydrodynamic Control of Alzheimer Aβ Fibrillation with Glucosaminic Acid Containing Click-Cyclized β-Bodies

“…13,14 Other reports indicate toxicity to be mainly due to predominant Aβ(1−40) probably through NCAM2 degradation and other Aβ-associated proteolytic activities. 15,16 Missense mutations of APP, PS1, and PS2 genes, and imbalanced APP processing can offset the homeostasis and increase the ratio of Aβ(1−42)/Aβ (1−40). This in turn results in erroneous downstream events such as Aβ(1−42) oligomerization and protein deposition, eventually leading to cognitive impairment and dementia.…”

“…Subsequently, primary amyloid nucleation leads to spherical oligomers and formation of larger donut shaped protofibrils, closely followed by construction of fibrils and precipitation in plaques. ,, Thus, an efficient catalytic cycle of fibrillation is established. A link between Alzheimer’s Disease (AD), an incurable and chronic neurodegenerative disorder, and the Aβ pathway was first proposed in 1991 with the amyloid-cascade hypothesis. − A homeostasis has been suggested between Aβ(1–40) and Aβ(1–42), produced by sequential cleavage by BACE1 and γ-secretase, in which Aβ(1–42) is believed to be the main cause of the neurotoxic effects. , Other reports indicate toxicity to be mainly due to predominant Aβ(1–40) probably through NCAM2 degradation and other Aβ-associated proteolytic activities. , Missense mutations of APP, PS1, and PS2 genes, and imbalanced APP processing can offset the homeostasis and increase the ratio of Aβ(1–42)/Aβ(1–40). This in turn results in erroneous downstream events such as Aβ(1–42) oligomerization and protein deposition, eventually leading to cognitive impairment and dementia. , Despite decades of studies, there is currently no direct proof linking the molecular mechanism of Aβ aggregation to neurodegeneration, and after innumerable failures, the community is questioning development of therapeutics targeting Aβ aggregation …”