The brain relies on the “housekeeping” systems of autophagy and lysosomes to keep cells healthy. Autophagy is the body’s cellular recycling system. It is the process by which old or damaged cell parts are broken down or recycled into new, usable cell parts. When autophagy kicks in, the cell wraps unwanted cell parts in a membrane, like putting trash in a bag. This “trash bag” is then delivered to the lysosome, a tiny digestive pouch within the cell. The lysosome breaks down the parts into their basic components, which the cell can reuse to build new cellular parts. In Alzheimer’s disease (AD), this cleanup system begins to fail. Harmful proteins such as tau start to build up inside neurons and disrupt how brain cells communicate. Many AD genetic risk factors point to these systems, suggesting that improving cellular cleanup could be a powerful way to slow or prevent the disease. One of the key controllers of this cleanup process is a protein called Transcription Factor EB (TFEB). TFEB acts as a master switch, turning on genes that build and maintain the cell’s waste-removal machinery. When TFEB is activated, cells do a better job of clearing out debris, including toxic tau aggregates. Although TFEB can be switched on by blocking a pathway called mTOR, long-term mTOR inhibition has serious side effects, so researchers are looking for safer ways to activate TFEB without touching mTOR.
Dr. Li and his group have made substantial progress toward this goal. They developed a sensitive test to detect when TFEB becomes activated and have used it to screen roughly 250,000 small molecules that promote its activation. From this work, they discovered a promising chemical family, imidazo[1,2-a]pyrazines, that boosts TFEB activity and improves cellular waste-clearing functions. Their lead compound, M112, helps TFEB move into the cell nucleus and activate cleanup genes, all without interfering with mTOR. These early findings suggest that the Li lab may have uncovered an entirely new way to trigger the brain’s natural cleanup systems. They hypothesize that these newly discovered small molecules can help neurons clear harmful tau by safely activating TFEB through an mTOR-independent mechanism.
They will test this hypothesis using two aims. In Aim 1, they will refine the chemical structures of imidazo[1,2-a]pyrazine molecules to identify the most effective and safe versions for activating the cleanup pathway in iPSC-induced neurons. In Aim 2, they will determine how these compounds work, how they activate TFEB, what proteins they interact with, and how they influence the cell’s ability to remove toxic material. They will assess the effects on TFEB activation (phosphorylation), identifying their molecular targets using photoaffinity probes, and performing proteomic analyses.
If successful, this work could lay the foundation for a completely new class of Alzheimer’s treatments, ones that strengthen the cell’s own defenses and promote the healthy clearance of tau without the risks associated with current approaches. It represents a compelling and innovative direction for therapeutic development in AD.
