We propose to explore a novel therapeutic concept for Alzheimer disease (AD) based on the promotion of clearance for pathologic proteins. Proteolysis-targeting chimeras (PROTACs) are hetero-bifunctional molecules that can bring the ubiquitin ligase (E3) into the vicinity of the protein of interest (POI), which results in the protein ubiquitination, followed by proteasomal degradation. PROTACs can be developed to target aberrant tau, α-synuclein, TDP43, intracellular amyloid β (Aβ), GSK-3β and other proteins involved in AD pathology. We hypothesis that well-developed PROTACs can be applied to the treatment of AD and other neurodegenerative diseases, to promote the clearance of pathologic proteins accumulated in the brain. Here we will use tau as an example. Published small-molecule tau-targeting PROTACs are using ligands binding to two common E3 ligases: von Hippel-Lindau protein (VHL) and cereblon (CRBN). But they are distributed in all tissues and target many proteins, not only tau. To develop more specific and potent PROTACs, we will first explore tau-targeting E3 ligases in human AD brains, choose suitable E3 ligase candidates, and develop novel ligands binding to tau or E3 ligases. Then we will use different linkers to combine ligands and design new PROTACs. The designed PROTACs will be screened for the expected ternary complex by molecular modeling. Ternary complexes will be subjected to molecular dynamics simulations to understand their stability, which is an important criterion for us to select PROTACs for synthesis. Protein-binding affinities and tau-reducing effects in vitro will be evaluated with follow-up structure-based optimization. The most potent PROTACs with the least off-target effects will move on to in vivo study. Specific aims: Aim 1: Explore tau-targeting E3 ligases in human AD brains by interaction proteomics and classical verification Aim 2: Development of novel PROTACs: screen and develop ligands binding to tau or E3 ligase, and design and synthesis PROTACs Aim 3: In vitro evaluation in cell models and structure-based hit-to-lead compound optimization Aim 4: In vivo evaluation of hit PROTACs: pharmacokinetic study and treatment effects in tau transgenic rT2/T2 mice model Overall, this project will increase our understanding of tau-targeting E3 ligases in AD brains, generate pre-clinical data for novel, disease-modifying PROTACs to combat pathologic proteins in AD and bring a novel class of small molecules into clinical translation. If successful, it will bring cost-effective new drugs for AD and other neurodegenerative diseases.