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NEUROPHARMACOLOGY

A Neuronal Microtubule-Interacting Agent, NAPVSIPQ, Reduces Tau Pathology and Enhances Cognitive Function in a Mouse Model of Alzheimer's Disease

Departments of Neurology (Y.M., A.J.G., L.M., C.H.-F., H.-F.L., L.F., P.S.A.), Biochemistry (L.L.), and Psychology (B.R.W.), Georgetown University Medical Center, Washington, District of Columbia; Adams Super Center for Brain Studies (I.G.), Elton Laboratory for Molecular Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel (Y.J., I.G.); Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York (E.P., O.A.); and Alzheimer's Disease Cooperative Study, Department of Neurosciences, University of California San Diego, School of Medicine, San Diego, California (P.S.A.)

Neurofibrillary tangles composed of aggregated, hyperphosphorylated tau in an abnormal conformation represent one of the major pathological hallmarks of Alzheimer's disease (AD) and other tauopathies. However, recent data suggest that the pathogenic processes leading to cognitive impairment occur before the formation of classic tangles. In the earliest stages of tauopathy, tau detaches from microtubules and accumulates in the cytosol of the somatodendritic compartment of cells. Either as a cause or an effect, tau becomes hyperphosphorylated and aggregates into paired helical filaments that comprise the tangles. To assess whether an agent that modulates microtubule function can inhibit the pathogenic process and prevent cognitive deficits in a transgenic mouse model with AD-relevant tau pathology, we administered the neuronal tubulin-preferring agent, NAPVSIPQ (NAP). Three months of treatment with NAP at an early-to-moderate stage of tauopathy reduced the levels of hyperphosphorylated soluble and insoluble tau. A 6-month course of treatment improved cognitive function. Although nonspecific tubulin-interacting agents commonly used for cancer therapy are associated with adverse effects due to their anti-mitotic activity, no adverse effects were found after 6 months of exposure to NAP. Our results suggest that neuronal microtubule interacting agents such as NAP may be useful therapeutic agents for the treatment or prevention of tauopathies.

Address correspondence to: Dr. Yasuji Matsuoka, Department of Neurology, Georgetown University Medical Center, 4000 Reservoir Road N.W., Washington, DC 20057. E-mail: ym56{at}georgetown.edu