Microtubule-associated protein tau is essential for long-term depression in the hippocampus

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.

Novel function of Tau in regulating the effects of external stimuli on adult hippocampal neurogenesis

“…Thus, it can be hypothesized that granule neurons are selectively affected by Tau deficiency in terms of their basal synaptic activity. In addition, alterations that may be related to deficient synaptic plasticity (LTP and LTD) have been reported in Tau −/− mice (Ahmed et al , 2014; Kimura et al , 2014; Regan et al , 2015). In fact, hippocampal LTD is considered necessary for clearing old memories, and Tau −/− mice show impairments in learning flexibility and various types of hippocampal‐dependent memory (Ikegami et al , 2000; Ahmed et al , 2014; Lei et al , 2014; Ma et al , 2014; Regan et al , 2015).…”

“…In contrast, EE reduced the number and size of the PSDs located on the 5 th branching order dendrites of Tau −/− neurons, which were already reduced under CH conditions in comparison with those of WT mice. Given that Tau −/− mice present impairments in both LTP (Ahmed et al , 2014) and LTD (Kimura et al , 2014), the reduction in the number and size of 5 th branching order PSDs in response to EE may be the consequence of two events. On one hand, due to inefficient LTP generation, EE might not be able to trigger a net increase in the formation of new PSDs.…”

“…It plays key roles in the establishment of neuronal polarity and migration during embryonic development (Caceres & Kosik, 1990; Dawson et al , 2001; Sapir et al , 2012; Sayas et al , 2015), in axonal transport (Ballatore et al , 2007; Hernandez & Avila, 2010) and in intracellular trafficking (Hernandez & Avila, 2010). Under physiological conditions, Tau is located mainly in axonal microtubules (Hirokawa et al , 1996; Aronov et al , 2001), although increasing evidence supports its presence also in dendrites (Ittner et al , 2010) and dendritic spines (Ittner et al , 2010; Mondragon‐Rodriguez et al , 2012; Kimura et al , 2014). The affinity of Tau to bind microtubules is finely regulated, depending mainly on the selective expression of various isoforms and post‐translational modifications.…”

Enduring Elevations of Hippocampal Amyloid Precursor Protein and Iron Are Features of β-Amyloid Toxicity and Are Mediated by Tau

“…Thus, lowering tau is a promising therapeutic concept for AD. However, chronic loss of tau itself causes impairment to long-term potentiation and long-term depression [8][9][10], and tau KO mice exhibit cognitive deficits as early as 4-6 months of age [8,10]. Aged tau KO mice (≥12 months old) have motor and cognitive impairment that accompanies brain David I. Finkelstein and Ashley I. Bush contributed equally to this work.…”

Glycogen Synthase Kinase 3β-mediated Phosphorylation in the Most C-terminal Region of Protein Interacting with C Kinase 1 (PICK1) Regulates the Binding of PICK1 to Glutamate Receptor Subunit GluA2

“…The hallmark of AD is the deposition of amyloid ␤ protein (A␤) (senile plaques) and hyperphosphorylated tau (neurofibrillary tangles) (13), both of which have been shown to be related to LTD. A␤ dimers inhibit long-term potentiation and induce LTD (14), and the presence of tau is required for LTD induction (15).…”