In Vivo Pharmacology

To understand the chemical underpinnings of a disease’s cellular pathology and mechanisms of action, in vivo pharmacology provides the ability to pull molecular hallmarks to the surface in measurable quantities which can yield pre-clinical information for potential treatments of cognitive diseases such as Frontotemporal Dementia (FTD), Progressive Supranuclear Palsy (PSP), and Alzheimer’s Disease (AD). Compound screening and validation using in vivo models of cognitive diseases has value in narrowing down molecular therapies for diseases treatment to provide precise therapy for these molecularly complicated diseases.
P301S mutant human tau transgenic mice have comparable behavioral, biochemical, and histological phenotypes to those of patients with Alzheimer’s Disease (AD). Using this transgenic animal line, Yoshiyama et al. 2007 has shown that not only do filamentous tau lesions develop in P301S mice at 6 months of age and progressively accumulates throughout their lifespan but also that hippocampal synapse loss and impaired synaptic function was detectable before tau tangles were present, consistent with human pathology. Our lab plans to employ this transgenic line to learn more about a class of targeted protein degraders, also known as Proteolysis Targeting Chimeras (PROTACS) that show promise in degradation of hyperphosphorylated tau aggregates (pathogenic tau). Recent work in our lab has shown that the PROTAC, QC-01-175, is successful in inducing ubiquitination and proteasomal degradation of pathogenic tau making this an exciting compound to test at an in vivo model. Click here to read more about the work done in our lab in regards to QC-01-175.