Drug Discovery

Anti-tangle

Valproate And Lithium to Inhibit Tau Pathophysiology

Investigator(s): Rebekah Loy, PhD and PeterTariot, MD

Institution(s): University of Rochester Medical Center, Rochester

Duration: 2002 - 2003

Summary:

Clinical-pathological correlations suggest that neurofibrillary tangles (NFTs) may be critical in the evolution of AD. NFTs consist of accumulations of abnormal proteins, especially paired helical filaments of the microtubule-associated protein tau, within neuronal cell bodies and processes. Abnormal phosphorylation of tau can lead to disrupted cytoskeletal function, abnormal protein trafficking, and cell death. Clarifying the mechanisms of abnormal phosphorylation of tau and reducing abnormally phosphorylated tau and/or tangle formation is a major therapeutic focus in AD. Valproate and lithium block the phosphorylation of tau in vitro by inhibiting the enzyme GSK-3ß, a potential drug discovery target for ADIn this program Dr. Loy and colleagues will test the effects of lithium and valproate in preventing or delaying NFT formation and associated loss of cognitive ability in two tangle forming mouse models of AD.A positive result, that a GSK3ß inhibitor delayed onset or reduced tau burden in either tauopathy mouse model, would provide strong proof of concept support for the first time that GSK-3ß is important in the pathogenesis of neurofibrillary tangle formation in AD. In addition, if successful, this study lead to new drug discovery approaches that build on valproate and/or lithium molecules as therapies to slow the cognitive decline associated with AD and other related dementias.