Deciphering the\nMorphological Difference of Amyloid‑β\nFibrils in Familial and Sporadic Alzheimer’s Diseases

The aggregation of amyloid-β (Aβ) into amyloid\nfibrils\nis the major pathological hallmark of Alzheimer’s disease (AD).\nAβ fibrils can adopt a variety of morphologies, the relative\npopulations of which are recently found to be associated with different\nAD subtypes such as familial and sporadic AD (fAD and sAD, respectively).\nThe two AD subtypes differ in their ages of onset, AD-related genetic\npredispositions, and dominant Aβ fibril morphologies. We postulate\nthat these disease subtype-dependent fibril morphology differences\ncan be attributed to the intrinsic fibril properties and interacting\nmolecules in the environment. Using atomistic discrete molecular dynamics\nsimulations, we demonstrated that the fAD-dominant morphology exhibited\na lower free-energy barrier for fibril growth but also a lower stability\ncompared with the sAD-dominant fibril morphology, resulting in the\ntime-dependent population change consistent with experimental observations.\nAdditionally, we studied the effect of the Bri2 BRICHOS domain, an\nendogenous protein that has been reported to inhibit Aβ aggregation\nby preferential binding to fibrils, as one of the possible environmental\nfactors. The Bri2 BRICHOS domain showed stronger binding to the fAD-dominant\nfibril than the sAD-dominant fibril <i>in silico</i>, suggesting\na more effective suppression of fAD-dominant fibril formation. This\nresult explains the high population of the sAD-dominant fibril morphology\nin sporadic cases with normal Bri2 functions. Genetic predisposition\nin fAD, on the other hand, might impair or overwhelm Bri2 functions,\nleading to a high population of fAD-associated fibril morphology.\nTogether, our computational findings provide a theoretical framework\nfor elucidating the AD subtypes entailed by distinct dominant amyloid\nfibril morphologies.