Emerging biophysical origins and pathogenic implications of amyloid oligomers
Hanxi Tang, Nikolaos K. Andrikopoulos, Yuhuan Li, Song-Hua Ke, Yunxiang Sun, Feng Ding, Pu Chun Ke
Abstract
The amyloid hypothesis has been a leading narrative concerning the pathophysiological foundation of Alzheimer’s and Parkinson’s disease. At the two ends of the hypothesis lie the functional protein monomers and the pathology-defining amyloid fibrils, while the early stages of protein aggregation are populated by polymorphic, transient and neurotoxic oligomers. As the structure and activity of oligomers are intertwined, here we show oligomers arising from liquid-liquid phase separation and β-barrel formation, their routes to neurodegeneration, and their role in cerebrovascular perturbation. Together, this Perspective converges on the multifaceted oligomer-axis central to the pathological origin and, hence, the treatment of amyloid diseases. For decades, research on Alzheimer’s disease and dementia has lacked a unified framework. This Perspective explores the convergence of key amyloid protein oligomerization processes that drive neurodegeneration and cerebrovascular damage, aiming to advance effective diagnosis and treatment of amyloid diseases.