THERAPEUTIC SUPERHEROES: SMALL MOLECULES TARGETING NEURODEGENERATION VIA THE p75 NEUROTROPHIN AND TRK B/C SIGNALING PATHWAYS

Abstract

Neurodegeneration is one of the most prominent diseases with no definitive cures in modern science to date. For years scientists have studied mechanisms to combat neurodegeneration—identifying key molecules and receptors involved in cell survival and apoptotic signaling—but no one has yet prevailed, until Dr. Frank Longo that is. Dr. Longo and his team at Stanford University are changing the trajectory of neurodegenerative therapeutics with a focus on “redirection” of degenerative signaling in the brain. Longo and team have identified two promising small molecule p75NTR and TrkB/C ligands which demonstrate capabilities to inhibit Alzheimer’s-related cell death while fortifying the remaining synapses against byproducts of degeneration. These molecules, namely “LM11A-31” and “BD10-2”, target the core of neurodegeneration (the signaling pathway) rather than the byproducts created in disease pathology. In this way, the LM11A-31 and BD10-2 small molecule therapeutics offer valuable insight into a hopeful future for combatting neurodegeneration. This thesis builds upon the research already conducted with the LM11A-31 therapeutic by investigating the therapetuic’s effects in a similar form of dementia (tauopathy mouse model) with the hopes of moving the small molecule into additional clinical trials targeting a broader class of neurodegeneration. Moreover, this thesis provides insight into another small molecule ligand in development by Dr. Longo, BD10-2, which targets TrkB/C signaling pathways with the goal of joining LM11A-31 in human clinical trials. Lastly, the research presented in this thesis investigates the effects of BD10-2 on microglia activation in the presence of neuroinflammation to gain insight into which pro-inflammatory and/or anti-inflammatory microglia phenotypes may be affected by treatment with BD10-2.