Phosphorylation in two discrete tau domains regulates a stepwise process leading to postsynaptic dysfunction.

Abstract

KEY POINTS\nTau mislocalization to dendritic spines and associated postsynaptic deficits are mediated through different and non-overlapping phosphorylation sites. Tau mislocalization to dendritic spines depends upon the phosphorylation of either Ser396 or Ser404 in the C-terminus. Postsynaptic dysfunction instead depends upon the phosphorylation of at least one of five residues in the proline-rich region of tau. The blockade of both gsk3β and cdk5 is required to prevent P301L-induced tau mislocalization to dendritic spines, supporting redundant pathways that control tau mislocalization to spines.\n\n\nABSTRACT\nTau protein consists of an N-terminal projection domain, a microtubule-binding domain, and a C-terminal domain. In neurodegenerative diseases, including Alzheimer s disease and frontotemporal dementia, the hyperphosphorylation of tau changes its shape, binding partners, and resulting function. An early consequence of tau phosphorylation by proline-directed kinases is postsynaptic dysfunction associated with the mislocalization of tau to dendritic spines. The specific phosphorylation sites leading to these abnormalities have not been elucidated. Here, using imaging and electrophysiological techniques to study cultured rat hippocampal neurons, we show that postsynaptic dysfunction results from a sequential process involving differential phosphorylation in the N-terminal and C-terminal domains. First, tau mislocalizes to dendritic spines, in a manner that depends upon the phosphorylation of either Ser396 or Ser404 in the C-terminal domain. Second, a reduction of functional AMPA receptors depends upon the phosphorylation of at least one of five residues (Ser202, Thr205, Thr212, Thr217, and Thr231) in the proline-rich region of the N-terminal domain. This is the first report of differential phosphorylation in distinct tau domains governing separate, but linked, steps leading to synaptic dysfunction. This article is protected by copyright. All rights reserved.