Dominant aggregation processes in the human brain

Determine which molecular processes identified under controlled in vitro conditions dominate pathological protein aggregate accumulation in the human brain and how those processes differ between healthy and diseased states.

Background

The paper frames the interpretation of pathological protein aggregation in humans as an inverse problem: aggregate-length distributions measured from tissue may provide mechanistic information, but the relevant microscopic processes operate in an open biological environment with ongoing protein synthesis, degradation, aggregate formation, and active clearance. In vitro studies have identified processes such as nucleation, elongation, fragmentation, and aggregate-catalysed self-replication, yet their relative importance in human disease remains unresolved.

The paper develops mathematical models showing how aggregate-length distributions can reflect the balance between aggregate growth, depolymerisation, fragmentation, and removal. However, the broader biological question of which molecular mechanisms actually dominate aggregate accumulation in the human brain, and how their contributions change between health and disease, is explicitly identified as unresolved.