Abstract
The microtubule-associated protein tau is a principal component of neurofibrillary tangles, and has been identified as a key molecule in Alzheimer's disease and other tauopathies. However, it is unknown how a protein that is primarily located in axons is involved in a disease that is believed to have a synaptic origin. To investigate a possible synaptic function of tau, we studied synaptic plasticity in the hippocampus and found a selective deficit in long-term depression (LTD) in tau knockout mice in vivo and in vitro, an effect that was replicated by RNAi knockdown of tau in vitro. We found that the induction of LTD is associated with the glycogen synthase kinase-3-mediated phosphorylation of tau. These observations demonstrate that tau has a critical physiological function in LTD.
Highlights
The microtubule-associated protein ‘tau’ (MAPT) gene is located on chromosome 17 and consists of 16 exons [1]
To investigate a possible synaptic function of tau, we studied synaptic plasticity in the hippocampus and found a selective deficit in long-term depression (LTD) in tau knockout mice in vivo and in vitro, an effect that was replicated by RNAi knockdown of tau in vitro
We have shown that low-frequency stimulation (LFS) used to elicit physiological LTD leads to enhanced phosphorylation of tau at the PHF-1 epitope, via a glycogen synthase kinase (GSK)-3b-dependent mechanism
Summary
The microtubule-associated protein ‘tau’ (MAPT) gene is located on chromosome 17 and consists of 16 exons [1]. License http://creativecommons.org/licenses/by/3.0/, which permits unrestricted use, provided the original author and source are credited Tauopathies, such as Alzheimer’s disease (AD), are characterized by widespread accumulation of hyperphosphorylated tau. It is generally believed that hyperphosphorylation of tau is the critical step in causing it to be missorted from the axon to dendrites, where it interferes with neuronal function [9]. Associated with this accumulation, there is a loss of synapses and eventually neurons [10,11]. These data suggest that tau phosphorylation is an essential component of LTD
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