Testing 17-AAG for Treating Fronto-Temporal Dementia
Investigator(s): Larry Baum, PhD
Institution(s): The Chinese University of Hong Kong
Duration: 2008 - 2009
Tau protein aggregates in Fronto-Temporal Dementia (FTD). Tau mutations can cause tau aggregation and model FTD in transgenic Drosophila and mice. Hsp70 and Hsp90 chaperones, which promote normal tau solubility, are decreased in tau transgenic mice. Geldanamycin binds Hsp90 and leads to degradation of insoluble tau chaperoned by Hsp90. 17-AAG is a less toxic derivative of geldanamycin that recently treated a mouse neurodegenerative disease by causing degradation of the mutant protein. We propose treating FTD animal models with 17-AAG. We have used transgenic Drosophila expressing wild-type and mutant tau, as well as transgenic mice expressing human mutant tau. By behavior tests, immunochemistry, and immunoblotting, we will detect the effect of 0.1%, 0.01%, 0.001%, or 0% 17-AAG in food on symptoms and pathology in transgenic Drosophila. We will treat 8 month-old mice expressing P301L tau with 25, 5, or 0 mg/kg 17-AAG by thrice weekly intraperitoneal injection for 4 months, and will detect treatment effects by tau immunohistochemistry and immunoblotting of soluble and insoluble fractions of tau. Successful tests could lead to human trials and a new treatment for FTD.