The microtubule-associated protein tau accumulates in Alzheimer's and other fatal dementias, which manifest when forebrain neurons die. Recent advances in understanding these disorders indicate that brain dysfunction precedes neurodegeneration, but the role of tau is unclear. Here, we show that early tau-related deficits develop not from the loss of synapses or neurons, but rather as a result of synaptic abnormalities caused by the accumulation of hyperphosphorylated tau within intact dendritic spines, where it disrupts synaptic function by impairing glutamate receptor trafficking or synaptic anchoring. Mutagenesis of 14 disease-associated serine and threonine amino acid residues to create pseudohyperphosphorylated tau caused tau mislocalization while creation of phosphorylation-deficient tau blocked the mistargeting of tau to dendritic spines. Thus, tau phosphorylation plays a critical role in mediating tau mislocalization and subsequent synaptic impairment. These data establish that the locus of early synaptic malfunction caused by tau resides in dendritic spines.
Bibliographical noteFunding Information:
We thank P. Higgins, S. Liu, J. Paulson, M. Schmidt, L. Kemper, T. Moroni, N. Anderson, and B. Dummer for expert technical assistance, Dr. R. Huganir (Johns Hopkins University) for the glutamate receptor antibodies, Dr. P. Davies (Albert Einstein College of Medicine) for the tau antibodies, and Dr. E. Kandel (Columbia University) for the activator mice. We would like to acknowledge the assistance of N. Shah and the Flow Cytometry Core Facility of the Masonic Cancer Center at the University of Minnesota, a comprehensive cancer center designated by the National Cancer Institute, supported in part by P30 CA77598. Sources of funding for this study include B. Grossman and her family, the American Health Assistance Foundation (D.L.), and the NIH (R01-DA020582, K02-DA025048 to D.L.; R01-NS049178 to L.M.L.; T32-DA007234 to R.D.P.; R01-NS049129 to L.-L.Y.; T32 DA022616-02 to M.N.R.; R01-AG026252, R01-NS063214 to K.H.A.).