Characterizing Pathogenic Protein Aggregates for Utilization as Molecular Tools to Accelerate Neurodegenerative Disease Research

Alzheimer’s and Parkinson’s diseases (AD, PD) are the two most common neurodegenerative disorders. Despite their debilitating effects and increasing prevalence in society, no cures are known. Both diseases are characterized by the presence of aggregates in the brain, which include alpha-synuclein, tau and amyloid beta proteins. These proteins normally have distinct functions in neurons, yet they share a common pathological mechanism – highly flexible monomers aggregate into oligomers and fibrils which form plaques in the brain. These aggregates are associated with neuronal cell death and seed further protein aggregation as disease progresses. To better study the role of these proteins in neurodegenerative disease, we developed consistent, scalable production methods to generate active alpha-synuclein, tau and amyloid beta oligomers and fibrils in vitro. We demonstrate that oligomers are toxic to primary cortical neuron cultures, while fibrils seed AD and PD pathology in a mouse brain. These recombinant protein aggregates have exciting potential for use as molecular tools in neurodegenerative disease models and drug discovery.

Learning Objectives:

1. Define key proteins aggregates present in Alzheimer’s and Parkinson’s diseases.

2. Explain how recombinant protein aggregates can be used to study neurodegenerative disease.