Pre-formed Fibrils (PFFs)--A Novel Approach to Modeling Neurodegeneration

Protein aggregation is a major pathological feature of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Under pathological conditions, Tau, Amyloid beta, alpha-synuclein, TDP-43, Huntingtin and other proteins integrate into a wide array of undesirable structures, ranging from oligomers and prefibrillar assemblies to highly ordered aggregates. The fibrillar structure represents a rapid growth phase of protein aggregation as these fibrils are “active” and rapidly recruit monomers for elongation. In additions, these fibrils randomly break into shorter fragments that could act as “seeds”, which transmits to other cells and independently recruits monomers to form novel fibrils. Pre-formed fibrils (PFFs) are in vitro formed active fibrils that have this "seeding" activity and are capable of continuously recruiting soluble endogenous pathological proteins to form aggregates and finally induce neurodegenerative pathologies.

The establishment of reliable disease models is crucial for discovering the pathological mechanisms, evaluating the efficacy of therapeutic interventions, and assessing the safety of drug candidates. Compared with traditional disease modeling approaches, PFFs induced pathology does not depend on gene editing, chemical or physical damage, and it can better mimic naturally occurring pathological states processes. Therefore, PFFs is a novel approach to modeling neurodegenerative diseases.