Deciphering the Morphological Difference of Amyloid-β Fibrils in Familial and Sporadic Alzheimer’s Diseases

• DOI: 10.1021/acs.jcim.4c01471
• Publication Date: 2024-10-09T13:10:56Z
• Authors: Gangtong Huang; Zhiyuan Song; Yun Xu; Yunxiang Sun; Feng Ding
• Keywords: Amyloid (mycology)

The aggregation of amyloid-β (Aβ) into amyloid fibrils is the major pathological hallmark Alzheimer's disease (AD). Aβ can adopt a variety morphologies, relative populations which are recently found to be associated with different AD subtypes such as familial and sporadic (fAD sAD, respectively). two differ in their ages onset, AD-related genetic predispositions, dominant fibril morphologies. We postulate that these subtype-dependent morphology differences attributed intrinsic properties interacting molecules environment. Using atomistic discrete molecular dynamics simulations, we demonstrated fAD-dominant exhibited lower free-energy barrier for growth but also stability compared sAD-dominant morphology, resulting time-dependent population change consistent experimental observations. Additionally, studied effect Bri2 BRICHOS domain, an endogenous protein has been reported inhibit by preferential binding fibrils, one possible environmental factors. domain showed stronger than silico, suggesting more effective suppression formation. This result explains high cases normal functions. Genetic predisposition fAD, on other hand, might impair or overwhelm functions, leading fAD-associated morphology. Together, our computational findings provide theoretical framework elucidating entailed distinct