Differential effect of three‐repeat and four‐repeat tau on mitochondrial axonal transport

Stoothoff, Will; Jones, P.; Spires‐Jones, Tara L.; Joyner, Daniel; Chhabra, Ekta Seth; Bercury, Kathryn K.; Fan, Zhanyun; Xie, Hong; Bacskai, Brian J.; Edd, Jon; Irimia, Daniel; Hyman, Bradley T.

doi:10.1111/j.1471-4159.2009.06316.x

Cited by 123 publications

(113 citation statements)

References 35 publications

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“…Among the different ways Tau might affect MAPK signaling are interactions with signaling protein complexes or alterations in microtubule-dependent growth factor receptor trafficking to the cell surface. Studies performed in vitro and in cells have suggested a role for Tau in axonal transport and vesicle trafficking where it has been found that the presence of Tau inhibited transport (57)(58)(59)(60)(61)(62)(63), whereas another study carried out in mice reported that the Tau level had no effect on transport (64). Based on these findings, one would not predict that Tau depletion would inhibit vesicle transport or lead to decreases in growth factor receptors (e.g.…”

Section: Discussionmentioning

confidence: 72%

Tau Potentiates Nerve Growth Factor-induced Mitogen-activated Protein Kinase Signaling and Neurite Initiation without a Requirement for Microtubule Binding

Leugers¹,

Lee

2010

Journal of Biological Chemistry

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Microtubule-associated protein Tau is known to bind to and stabilize microtubules, thereby regulating microtubule dynamics. However, recent evidence has indicated that Tau can also interact with various components of intracellular signaling pathways, leading to the possibility that Tau might have a role in signal transduction. Here we provide evidence that during growth factor stimulation of neuronal cells, Tau has functions in advance of the neurite elongation stage. Using Tau-depleted neuronal cell lines, we demonstrate that Tau is required for neurite initiation in a manner that does not involve its microtubule binding function. In addition, we demonstrate that Tau potentiates AP-1 transcription factor activation in response to nerve growth factor (NGF). The effect of Tau on AP-1 activation is mediated through its ability to potentiate the activation of mitogen-activated protein kinase (MAPK), which occurs in response to both NGF and epidermal growth factor. Phosphorylation of Tau at Thr-231 also occurs in response to NGF and is required for Tau to impact on MAPK signaling, whereas the ability of Tau to bind to microtubules is not required. Together, these findings indicate a new functional role for Tau in early neuronal development independent of its established role in microtubule stabilization.Microtubule-associated proteins are a class of proteins that includes Tau, MAP2, and MAP4. These proteins are so named for their ability to bind to and stabilize microtubules, thereby contributing to the regulation of microtubule dynamics. Tau in particular has been extensively studied due to its prominent role in the pathogenesis of neurodegenerative diseases such as Alzheimer disease and the fronto-temporal dementias (reviewed in Refs. 1-4). In general, research into the physiological functions of Tau has focused on its interactions with microtubules. However, additional roles for Tau beyond those associated with microtubules have been suggested by numerous studies. We have previously demonstrated that the amino terminus of Tau, a domain not involved in microtubule binding, is associated with the plasma membrane and can affect nerve growth factor (NGF) 2 -induced neurite outgrowth (5). Also, neurite outgrowth was shown to require phosphorylation of Tau at Ser-262, a modification that reduces the ability of Tau to bind to microtubules (6). In addition, interactions between Tau and various signaling proteins such as Src, Fyn, Abl, the p85 subunit of phosphatidylinositol 3-kinase, phospholipase C␥, 14-3-3, and Grb2 have been described (7-12). Such findings suggest that non-microtubule-associated Tau species may be associated with signaling components at the plasma membrane during early neurogenesis and differentiation. Recent reports have also indicated that Tau can be linked to the increased expression of cell cycle proteins. Mice expressing human Tau in the absence of mouse Tau and mice expressing FTDP-17 mutant Tau were found to have abnormal expression of cell cycle proteins (13-15) and a cell culture model expres...

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Section: Discussionmentioning

confidence: 72%

Tau Potentiates Nerve Growth Factor-induced Mitogen-activated Protein Kinase Signaling and Neurite Initiation without a Requirement for Microtubule Binding

Leugers¹,

Lee

2010

Journal of Biological Chemistry

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“…The mechanisms of this effect appear to be related with potentiation of autophagy, without excluding other possibilities, such as improvement of the redox state. Excess tau, which is present in some human fronto-temporal dementias and in PK −/− /Tau VLW mice, blocks the intracellular traffic of organelles, diminishes axonal transport, and impairs microtubule dynamics [46][47][48][49]. Autophagic vesicles accumulate in large numbers when fusion of autophagosomes with lysosomes is slowed by disrupting their transport in microtubules with vinblastine or nocodazole [50,51].…”

Section: Discussionmentioning

confidence: 99%

Natural Cannabinoids Improve Dopamine Neurotransmission and Tau and Amyloid Pathology in a Mouse Model of Tauopathy

Casarejos

Perucho

Gómez

et al. 2013

JAD

108

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Abstract. Cannabinoids are neuroprotective in models of neurodegenerative dementias. Their effects are mostly mediated through CB1 and CB2 receptor-dependent modulation of excitotoxicity, inflammation, oxidative stress, and other processes. We tested the effects of Sativex ® , a mixture of 9 -tetrahydrocannabinol and cannabidiol, acting on both CB1 and CB2 receptors, in parkin-null, human tau overexpressing (PK −/− /Tau VLW ) mice, a model of complex frontotemporal dementia, parkinsonism, and lower motor neuron disease. The animals received Sativex ® , 4.63 mg/kg, ip, daily, for one month, at six months of age, at the onset of the clinical symptoms. We evaluated the effects of Sativex ® on behavior, dopamine neurotransmission, glial activation, redox state, mitochondrial activity, and deposition of abnormal proteins. PK −/− /Tau VLW mice developed the neurological deficits, but those treated with Sativex ® showed less abnormal behaviors related to stress, less auto and hetero-aggression, and less stereotypy. Sativex ® significantly reduced the intraneuronal, MAO-related free radicals produced during dopamine metabolism in the limbic system. Sativex ® also decreased gliosis in cortex and hippocampus, increased the ratio reduced/oxidized glutathione in the limbic system, reduced the levels of iNOS, and increased those of complex IV in the cerebral cortex. With regard to tau and amyloid pathology, Sativex ® reduced the deposition of both in the hippocampus and cerebral cortex of PK −/− /Tau VLW mice and increased autophagy. Sativex ® , even after a short administration in animals with present behavioral and pathological abnormalities, improves the phenotype, the oxidative stress, and the deposition of proteins in PK −/− /Tau VLW mice, a model of complex neurodegenerative disorders.

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“…19 -21 We previously found in cultured neurons that alterations in axonal transport due to soluble tau over-expression resulted in perinuclear clumping of mitochondria. 18 Disruptions in mitochondrial distribution, morphology and function have been linked to several Supported by National Institute of Health Grants AG08487, T32AG000277, AG026249, K99AG33670, P50AG05134 and the Alzheimer's Association Zenith Award.…”

mentioning

confidence: 99%

“…8 -12 Meanwhile, tau overexpression, which results in abnormally high levels of soluble tau throughout the cell in the absence of aggregates, alters fast axonal transport, particularly in the anterograde or kinesin-dependent direction. [13][14][15][16][17][18] This transport deficit is thought to lead to depletion of necessary materials, deterioration of the synapse, and a "dying back" of the neuron. 19 -21 We previously found in cultured neurons that alterations in axonal transport due to soluble tau over-expression resulted in perinuclear clumping of mitochondria.…”

mentioning

confidence: 99%

Tau Accumulation Causes Mitochondrial Distribution Deficits in Neurons in a Mouse Model of Tauopathy and in Human Alzheimer's Disease Brain

Kopeikina

Carlson

Pitstick

et al. 2011

The American Journal of Pathology

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228

193

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Neurofibrillary tangles (NFT), intracellular inclusions of abnormal fibrillar forms of microtubule associated protein tau, accumulate in Alzheimer's disease (AD) and other tauopathies and are believed to cause neuronal dysfunction, but the mechanism of tau-mediated toxicity are uncertain. Tau overexpression in cell culture impairs localization and trafficking of organelles. Here we tested the hypothesis that, in the intact brain, changes in mitochondrial distribution occur secondary to pathological changes in tau. Array tomography, a high-resolution imaging technique, was used to examine mitochondria in the reversible transgenic (rTg)4510, a regulatable transgenic, mouse model and AD brain tissue. Mitochondrial distribution is progressively disrupted with age in rTg4510 brain, particularly in somata and neurites containing Alz50-positive tau aggregates. Suppression of soluble tau expression with doxycycline resulted in complete recovery of mitochondrial distribution, despite the continued presence of aggregated tau. The effect on mitochondrial distribution occurs without concomitant alterations in neuropil mitochondrial size, as assessed by both array tomography and electron microscopy. Similar mitochondrial localization alterations were also observed in human AD tissue in Alz50؉ neurons, confirming the relevance of tau to mitochondrial trafficking observed in this animal model. Because abnormalities reverted to normal if soluble tau was suppressed in rTg4510 mice, even in the continued presence of fibrillar tau inclusions, we suggest that soluble tau plays an important role in mitochondrial abnormalities, which likely contribute to neuronal dysfunction in AD.

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Differential effect of three‐repeat and four‐repeat tau on mitochondrial axonal transport

Cited by 123 publications

References 35 publications

Tau Potentiates Nerve Growth Factor-induced Mitogen-activated Protein Kinase Signaling and Neurite Initiation without a Requirement for Microtubule Binding

Tau Potentiates Nerve Growth Factor-induced Mitogen-activated Protein Kinase Signaling and Neurite Initiation without a Requirement for Microtubule Binding

Natural Cannabinoids Improve Dopamine Neurotransmission and Tau and Amyloid Pathology in a Mouse Model of Tauopathy

Tau Accumulation Causes Mitochondrial Distribution Deficits in Neurons in a Mouse Model of Tauopathy and in Human Alzheimer's Disease Brain

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