Mechanisms of Activity-Dependent Tau Release: The Role of Tau Interacting Proteins - Project Summary A key pathological hallmark of Alzheimer’s disease (AD) is the formation of intracellular neurofibrillary tangles (NFTs), composed of hyperphosphorylated and aggregated tau. The temporal and spatial progression of NFTs in the human brain closely correlates with AD severity. In recent years, an emerging prion-like model of tau propagation has gained attention, suggesting that tau spreads trans-synaptically between connected neurons, contributing to disease progression. However, the precise mechanisms governing this spread remain poorly understood. Increasing evidence links neuronal hyperexcitability to early AD pathogenesis. Although tau is primarily an intracellular protein, it can be released into the extracellular space upon neuronal activation. Understanding the molecular mechanisms underlying activity-dependent tau release is therefore of significant interest. This study aims to elucidate the mechanisms of tau release driven by neuronal hyperexcitability, using a Drosophila model and human neural cell lines. Aim 1 is to investigate the mechanism of activity-dependent tau release from neurons and synapses. Our preliminary data show that human tau (hTau) release from Drosophila neuromuscular junctions (NMJs) is synaptic transmission-dependent. Given previous evidence of trans-synaptic tau propagation, we hypothesize that synaptic vesicle proteins (e.g., Synaptogyrin, SV2A, etc.) regulate tau release. This aim will focus on pre-selected synaptic vesicle proteins with known tau interactions. Aim 2 is to identify and characterize novel tau- interacting proteins involved in activity-dependent tau release using an unbiased protein interactome approach. Unlike Aim 1, which tests pre-selected candidates, Aim 2 will examine newly identified proteins resulting from proteomic screening to uncover additional regulators of tau release. Aim 3 is to validate and extend findings from Aims 1 and 2 in a human neural cell line that endogenously expresses tau, ensuring translational relevance. Successful completion of this project will provide critical insights into the mechanisms of tau release and propagation, offering novel therapeutic targets for AD and other tauopathies.
