(443f) Novel Probe for Tau and ?-Synuclein Aggregation to Study Inter-Neuronal Fibril Transmission

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are most common types of neurodegenerative diseases in elder population. Recent studies have shown that aggregation of misfolded proteins is associated with disease progression of AD and PD. Tau pathology, including tau hyperphosphorylation and the formation of neurofibrillary tangles (NFT) exhibit a strong correlation with cognitive impairment. NFTs accumulated at different brain regions with progression of AD, suggesting transmission aberrant protein aggregations. Similarly, PD is characterized by the formation of Lewy body neurite, which is also know as accumulation of hyperphosphorylated and misfolded α-synuclein protein. Therefore, accumulation of misfolded protein, including tau and α-synuclein are key to the progression of AD and PD. However, the mechanisms underlying accumulation of protein aggregation and its intraneuronal transmission thus lead to disease propagation remains elusive. In this study, we developed novel FRET sensors to quantitatively detect tau and α-synuclein aggregation from neuronal culture media. The sensitivity of FRET sensor reporter line was engineered by overexpressing surface receptor, such as low-density lipoprotein receptor-related protein 1 (LRP1) and heparan sulfate proteoglycans (HSPGs). The FRET sensors were then integrated into iPSC derived glutaminergic or dopaminergic neuron culture to monitor endogenous formation of tau or α-synuclein aggregation, respectively, upon treatment with preformed fibrils. In summary, we developed novel tools for detection of tau and α-synuclein aggregation in vitro and thus enables further quantitative study of fibril transmission between neurons.