Tau Phosphorylation at Serine 396 Residue Is Required for Hippocampal LTD

Regan, Philip; Piers, Thomas M.; Yi, Jee Hyun; Kim, Dong-Hyun; Huh, Seonghoo; Park, Se Jin; Ryu, Jong Hoon; Whitcomb, Daniel J.; Cho, Kwangwook

doi:10.1523/jneurosci.2842-14.2015

Cited by 168 publications

(200 citation statements)

References 58 publications

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“…Our group have shown that electrically driven synaptic activity elicits an increase in tau phosphorylation at serine residues 396 and 404, with no change in phosphorylation at serine 202 and threonine 205 residues (Kimura and others, 2014;Regan and others, 2015). This finding differs somewhat from the previously described study.…”

Section: The Phosphorylation Signature Of Taucontrasting

confidence: 83%

“…In vivo and ex vivo electrophysiological recordings revealed a selective deficit in LTD, but not LTP, from the brains of mice with a homozygous or heterozygous tau deletion, but not from their wild-type counterparts (Kimura and others, 2014). Corroborating these findings, acute suppression of tau with tau-shRNA prevented the expression of LTD, and not LTP, in neurons from organotypic cultured hippocampal slices (Kimura and others, 2014;Regan and others, 2015). An important aspect of this in vitro study was the acute and sparse ablation of tau, largely restricted to CA1 neurons of the hippocampal slice.…”

Section: Tau Regulation Of Synaptic Functionmentioning

confidence: 83%

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Physiological and Pathophysiological Implications of Synaptic Tau

2016

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Tauopathies encompass a broad range of neurodegenerative diseases featuring extensive neuronal death and cognitive decline. However, research over the past thirty years has failed to significantly advance our understanding of how tau causes dementia, limiting the design of rational therapeutics. It has become evident that we need to expand our understanding of tau in physiology, in order to delineate how tau may contribute to pathology. This review will discuss recent evidence that has uncovered a novel aspect of tau function, based on its previously uncharacterised localisation to the synapse. Here, multiple streams of evidence support a critical role for synaptic tau in the regulation of synapse physiology. In particular, long-term depression, a form of synaptic weakening, is dependent on the presence of tau in hippocampal neurons. The regulation of tau by specific phosphorylation events downstream of GSK-3β activation appears to be integral to this signalling role. We will also describe how the regulation of synapse physiology by tau and its phosphorylation may inform our understanding of tauopathies and co-morbid diseases. This work should provide a platform for future tau biology research in addition to therapeutic design.

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Section: The Phosphorylation Signature Of Taucontrasting

confidence: 83%

Section: Tau Regulation Of Synaptic Functionmentioning

confidence: 83%

Physiological and Pathophysiological Implications of Synaptic Tau

2016

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“…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). Remarkably, it has been described that granule neurons are important for flexibility of learning strategies (Garthe et al , 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, this effect was not detected in Tau −/− animals. In this regard, Regan et al (2015) demonstrated that Tau −/− mice present basal deficits in AMPA internalization. This observation is in agreement with our results, since we observed unchanged levels of GluR1 in these mice after the Porsolt test.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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Tau is a microtubule‐associated neuronal protein found mainly in axons. However, its presence in dendrites and dendritic spines is particularly relevant due to its involvement in synaptic plasticity and neurodegeneration. Here, we show that Tau plays a novel in vivo role in the morphological and synaptic maturation of newborn hippocampal granule neurons under basal conditions. Furthermore, we reveal that Tau is involved in the selective cell death of immature granule neurons caused by acute stress. Also, Tau deficiency protects newborn neurons from the stress‐induced dendritic atrophy and loss of postsynaptic densities (PSDs). Strikingly, we also demonstrate that Tau regulates the increase in newborn neuron survival triggered by environmental enrichment (EE). Moreover, newborn granule neurons from Tau−/− mice did not show any stimulatory effect of EE on dendritic development or on PSD generation. Thus, our data demonstrate that Tau−/− mice show impairments in the maturation of newborn granule neurons under basal conditions and that they are insensitive to the modulation of adult hippocampal neurogenesis exerted by both stimulatory and detrimental stimuli.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Lei

Tuo

et al. 2015

Neurotherapeutics

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The amyloid cascade hypothesis of Alzheimer's disease (AD) positions tau protein as a downstream mediator of β-amyloid (Aβ) toxicity This is largely based on genetic cross breeding, which showed that tau ablation in young (3-7-month-old) transgenic mice overexpressing mutant amyloid precursor protein (APP) abolished the phenotype of the APP AD model. This evidence is complicated by the uncertain impact of overexpressing mutant APP, rather than Aβ alone, and for potential interactions between tau and overexpressed APP. Cortical iron elevation is also implicated in AD, and tau promotes iron export by trafficking APP to the neuronal surface. Here, we utilized an alternative model of Aβ toxicity by directly injecting Aβ oligomers into the hippocampus of young and old wild-type and tau knockout mice. We found that ablation of tau protected against Aβ-induced cognitive impairment, hippocampal neuron loss, and iron accumulation. Despite injected human Aβ being eliminated after 5 weeks, enduring changes, including increased APP levels, tau reduction, tau phosphorylation, and iron accumulation, were observed. While the results from our study support the amyloid cascade hypothesis, they also suggest that downstream effectors of Aβ, which propagate toxicity after Aβ has been cleared, may be tractable therapeutic targets.

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Tau Phosphorylation at Serine 396 Residue Is Required for Hippocampal LTD

Cited by 168 publications

References 58 publications

Physiological and Pathophysiological Implications of Synaptic Tau

Physiological and Pathophysiological Implications of Synaptic Tau

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

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

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