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

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