Parallel in-register contact propensity predicts the Amyloidogenicity of ADan and ABri in familial dementias.

Familial Danish dementia (FDD) and British dementia (FBD) are rare neurodegenerative diseases caused by stop-codon mutations in the Bri2 gene, leading to amyloid deposits formed by the aggregation of mutant ADan and ABri peptides, respectively. FDD symptoms usually manifest decades earlier than those of FBD. Probably due to the rarity of these conditions, the aggregation mechanisms of ADan and ABri and the molecular basis for FDD's earlier onset remain underexplored. Here, we computationally investigated the conformational dynamics of monomeric wild-type Bri23 and the two mutants ADan and ABri, as well as their self-assembly dynamics from dimers to hexamers using atomistic discrete molecular dynamics simulations. Our results aligned with earlier experimental work on the monomeric structures. We also confirmed that Bri23 is less amyloidogenic, showing significantly lower self-assembly propensity compared to ADan and ABri, which both favored forming β-sheet-rich oligomers. In amyloid aggregation, the critical nucleation event involves the transition from unaligned or misaligned oligomers to well-aligned fibril seeds featuring parallel in-register (PAIR) intermolecular β-sheets - the structural hallmark of mature fibrils. Notably, ADan showed a higher propensity than ABri to form longer PAIR intermolecular β-sheets within oligomers, suggesting a lower fibril nucleation barrier (i.e., higher amyloidogenicity) and thereby explaining FDD's earlier onset. We further identified nucleation "hotspots" with high PAIR propensities in both ADan and ABri, which may serve as potential therapeutic targets. Together, these insights into the early aggregation dynamics of these rare dementias enhance our understanding of the aggregation-nucleation process and disease mechanisms.