Study of the New HDAC i SW as a Treatment for Alzheimer's Disease and Other Tauopathies

ABSTRACT Alzheimerandapos s and other tauopathies are medical problems growing to historical proportions that threaten the long term viability of medical care systems world wide Alzheimerandapos s costs today are of the US GDP and growing as the population ages Effective disease modifying treatments have yet to be developed A number of drugs in clinical testing target amyloid but very few have been developed to target tau We expect that like heart disease cancer and HIV effective Alzheimerandapos s management will require combination treatment using multiple therapeutic modalities Prior work by our research team has determined that part of the tau phenotype can be reduced using a histone deacetylase HDAC inhibitor Tubastatin A TA This involved treatment of Tg mice that develop tau deposits by mo and forebrain atrophy by mo of age We treated mice from to mo and found improved behavioral performance and reduced total tau deposition However other components of the tau phenotype in this model were not significantly impacted Here we propose to test whether an improved HDAC inhibitor SW can more completely rescue the tau phenotype in this mouse SW has a higher affinity slightly longer half life and substantially increased brain permeability than TA SW is a new HDAC inhibitor with selectivity similar to that of TA but increased CNS penetration SW further lacks mutagenicity in the Ames test in which TA was positive Thus we wish to evaluate if this compound as well as a newly designed back up analog can more fully reverse the phenotype of the Tg mouse by pursuing the three aims below Aim Prepare new analogs of SW as potential back up compounds and conduct HDAC isozyme testing tubulin acetylation assays and ADMET assays Advance the best of these to animal studies in Aim Aim Conduct a dose range finding study of SW and the best back up compound from Aim to identify a dose in mouse chow that causes maximal CNS impact and is well tolerated Aim Test SW and the back up analog from Aim in Tg mice starting at two ages to ascertain the extent to which these new chemical entities can retard the development of the tau phenotype and whether benefits can be observed even after tau deposition has started Assessments will thus be made of drug effects on cognition histological tau deposition and neurochemical tau accumulation Any positive effects observed using these drugs after tau deposition would suggest benefit for people who already have dementia There are several potential mechanisms by which HDAC may produce benefits First it may lead to more stable microtubules and enhance axonal transport through increased tubulin acetylation Second it may increase tau degradation in the proteasome through increased HSP acetylation Third it may inhibit tau aggregation through increased tau acetylation We will monitor acetylation of each of these HDAC substrates to begin understanding the mechanism s most responsible for benefiting the tau phenotype in this model Project Narrative There are no effective treatments for the accumulation of abnormal proteins loss of memory and brain shrinkage that occur in Alzheimerandapos s disease and other tauopathy related neurodegenerative diseases This project will further establish the ability of brain penetrant HDAC inhibitors to serve as potential AD therapies using a relevant mouse model Success in this project will provide further validation of this therapeutic approach and lay a strong foundation for moving such NCEs to the clinic