Reducing protein aggregates is essential for slowing the progression of frontotemporal dementia (FTD) and related diseases. Drugs that can enhance protein degradation processes in the lysosomal compartment have been shown to reduce FTD-related tau aggregates in a brain slice model, and to promote recovery of synaptic markers found to be lost in correspondence with tau accumulation. Proof-of-principle studies previously established lysosomal modulation as a potential pharmacological strategy against tau-related pathology. The proposed research will synthesize and screen for potent lysosomal modulators as part of a unique drug discovery collaboration aimed at treating FTD. The collaboration consists of a faculty member in Pharmacology and the Center for Drug Discovery, and a member in Pharmaceutical Sciences/Medicinal Chemistry. Of several routes being pursued for reducing tau aggregates, the collaboration has described a lysosomal avenue that can be enhanced through small molecule modulators. Such modulators produce 3- to 9-fold increases in lysosomal cathepsins and other enzymes involved in protein clearance processes. This induced enhancement of lysosomal capacity was found to promote clearance of pathogenic tau and other aggregating protein species. In addition, the positive lysosomal modulation resulted in the restoration of cellular integrity, synaptic composition, and improved brain functionality in transgenic mouse models. The objective of the proposed experiments is to identify potentially disease modifying lead compounds, testing among new derivatives of first-generation modulators. The project will synthesize novel modulators designed through structure-activity relationships, taking advantage of a screening process in a brain slice model that allows the sensitive measure of enzyme up-regulation, pathogenic tau clearance, and synaptic protection. Lysosomal modulators will be first-in-class drugs for treating neurodegenerative disorders in order to slow or reverse cognitive decline.