Neurofibrillary tangles (NFTs) are biomarkers for Alzheimer’s disease and are the products of a breakdown in part of the structure of cells (Tau), leading to neural cell death. The goal of this project is to establish the first cellular system that develops authentic NFT-like Tau aggregates to provide mechanistic insights into NFT pathogenesis and a potential tool for identifying Tau- based therapeutics.
Over the past year, we have firmly established a cell-based model of neurofibrillary tangle formation. NFTs in Alzheimer’s disease and related Tauopathies are comprised of insoluble hyperphosphorylated Tau protein, but the mechanisms underlying the conversion of highly soluble Tau into insoluble NFTs remain elusive. Dr. Lee has, with Cure Alzheimer’s Fund funding, conducted a series of experiments demonstrating that introducing minute quantities of misfolded preformed Tau fibrils (Tau pffs) into Tau-expressing cells will rapidly recruit large amounts of soluble Tau into filamentous inclusions (resembling NFTs) with unprecedented efficiency. This suggests a “seeding” recruitment process as a highly plausible mechanism underlying NFT formation in vivo. Consistent with the emerging concept of prion-like transmissibility of disease-causing amyloidogenic proteins, we found that spontaneous uptake of Tau pffs into cells is likely mediated by endocytosis, suggesting a potential mechanism for the propagation of Tau lesions.