Mapping proteomic changes of tauopathy in human neurons

Weill Medical Coll Of Cornell Univ, New York NY

Investigators

Abstract

The accumulation and propagation of tau aggregates are key drivers of cognitive decline in Alzheimer’s disease (AD) and frontotemporal dementia (FTD). However, our knowledge of underlying mechanisms is not yet refined enough to meet the urgent clinical need for treatment. There is an urgent need to understand the mechanisms underlying propagation of tau aggregates. Ratios of 3R/4R are altered by FTD mutations, suggesting differential roles of 3R and 4R in tau pathogenesis. We recently showed that Tau-seeded 4R-P301S human neurons develop highly robust and progressively Tau aggregation , recapitulating many aspects of Tau pathology in AD. We also uncovered the critical roles of retromer in limiting and UFMylation cascade in promoting tau propagation. However, the cellular mechanisms underlying Tau propagation in AD are mostly unknown though likely affected by amyloid β (Aβ). Our overall objective is to discover AD-relevant cellular machinery underlying the propagation of misfolded tau aggregates in human neurons using unbiased proteogenomic approaches. To this end, we propose to combine ascorbic acid peroxidase (APEX), affinity purification mass spectrometry (AP-MS), and transcriptomics with our newly generated knockin hiPSC lines that express 3R/4R and 4R-P301S Tau. We propose three Specific Aims. Aim 1 will determine Tau interactomes influenced by amyloid and Tau seeding in Tau isoforms, using advanced proteomic techniques and deep learning analyses to prioritize genetic candidates. This will be validated in induced neurons and AD brains. Aim 2 will focus on the role of VPS29 in tau aggregation, examining its impact on proteomic and transcriptomic profiles, and integrate this data with human AD datasets to identify key molecular drivers. Aim 3 will explore how UFMylation regulates tau aggregation, mapping its effects on proteomic profiles and interactions with the retromer pathway, aiming to identify and test potential chemical interventions in AD human neuronal models. The proposed work will be led by three teams with complementary expertise in close collaboration. Gan lab will create proposed human iPSC neuronal and directly-programmed iN models, conduct transcriptomic profiling, and execute various cell treatments alongside interactome purification and validation experiments. Yu lab will perform AP-IP, APEX2-MS, and proteomics. Cheng lab will integrate genetic and proteomic data to prioritize genetics-driven candidate genes and pathways influencing Tau pathology using network topology-based deep learning analyses and Mendelian randomization techniques. Successful completion of the proposed study will provide unprecedented insight into AD-related tau pathology and pave the way for novel therapeutic strategies.