Characterizing Pathology-Inducing Protein Aggregates as Tools for Alzheimer's and Parkinson's Disease Models and Drug Discovery

Alzheimer’s and Parkinson’s diseases (AD, PD) are the two most common neurodegenerative disorders. Despite their debilitating effects and increasing prevalence in our society, no cure is 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 involving aggregation into oligomers and fibrils that form plaques in the brain.  Alpha-synuclein, tau and amyloid beta aggregates are associated with neuronal cell death and seed additional plaques as disease progresses. A key goal in advancing AD/PD drug discovery is developing disease models that effectively mimic the pathology observed in vivo. We developed consistent, scalable production methods to generate active alpha-synuclein, tau and amyloid beta oligomers and fibrils in vitro. We demonstrate that recombinant alpha synuclein aggregates are toxic to primary cortical neuron cultures, are transferred between neurons, and induce Parkinson’s pSer129 pathology in mouse brains. Further, we show that recombinant tau aggregates induce Alzheimer’s pSer202/pThr205 pathology in mouse brains, and synthetic amyloid beta aggregates are toxic to primary rat cortical neurons.  These molecular tools demonstrate exciting utility for seeding pathology in AD/PD disease models and facilitating primary research and drug discovery.

Learning Objectives:

1. Define key proteins aggregates targeted by Alzheimer’s and Parkinson’s disease drug development efforts.

2. Explain how protein aggregates are utilized to develop novel Alzheimer’s and Parkinson’s disease models.