Clogging of axons by tau, inhibition of axonal traffic and starvation of synapses

Mandelkow, Eckhard; Stamer, Karsten; Vogel, Robert; Thies, Edda

doi:10.1016/j.neurobiolaging.2003.04.007

Cited by 356 publications

(266 citation statements)

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“…The phosphorylation state of tau-which critically controls its physiopathology leading to selfaggregation and/or reduced assembly and stability of microtubules used as tracks for axonal trafficking (Stoothoff et al, 2005)-is also regulated by NGF deprivation in vitro (Nuydens et al, 1997;Shelton and Johnson, 2001) as well as in vivo Capsoni et al, 2002a,b). Moreover, since tau controls the bidirectionality of axonal motor-driven transport in a concentration-dependent manner and differentially modulates the kinesin and dynein activity along microtubule tracks (Dixit et al, 2008), defective intracellular trafficking of cargoes, including NTFs, could be due to an increased expression level of this protein (Ebneth et al, 1998;Stamer et al, 2002;Mandelkow et al, 2003) or to its altered intracellular localization (Thies et al, 2007) or hyperphosphorylation (Tatebayashi et al, 2004;Alonso et al, 1997). To this regard, the finding that the retrograde transport of I-125-NGF and activated Trk receptors is inhibited by colchicine-a drug that interferes with the polymerization of microtubules (Watson et al, 1999;Sandow et al, 2000)-suggests that an altered function of tau protein may account for age-related deficiency of long-range NTF signaling in cholinergic neurons.…”

Section: Ngf and Tau Protein Metabolismmentioning

confidence: 99%

Nerve growth factor as a paradigm of neurotrophins related to Alzheimer's disease

Calissano

Matrone

Amadoro

2010

Developmental Neurobiology

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Converging lines of evidence on the possible connection between NGF signaling and Alzheimer's diseases (AD) are unraveling new facets which could depict this neurotrophin (NTF) in a more central role. AD animal models have provided evidence that a shortage of NGF supply may induce an AD-like syndrome. In vitro experiments, moreover, are delineating a possible temporal and causal link between APP amiloydogenic processing and altered post-translational tau modifications. After NGF signaling interruption, the pivotal upstream players of the amyloid cascade (APP, b-secretase, and active form of c-secretase) are up-regulated, leading to an increased production of amyloid b peptide (Ab) and to its intracellular aggregation in molecular species of different sizes. Contextually, the Ab released pool generates an autocrine toxic loop in the same healthy neurons. At the same time tau protein undergoes anomalous, GSKb-mediated, phosphorylation at specific pathogenetic sites (Ser262 and Thr 231), caspase(s) and calpain-I-mediated truncation, detachment from microtubules with consequent cytoskeleton collapse and axonal transport impairment. All these events are inhibited when the amyloidogenic processing is reduced by b and c secretase inhibitors or anti-Ab antibodies and appear to be causally correlated to TrkA, p75CTF, Ab, and PS1 molecular association in an Ab-mediated fashion. In this scenario, the so-called trophic action exerted by NGF (and possibly also by other neurotrophins) in these targets neurons is actually the result of an anti-amyloidogenic activity. '

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Section: Ngf and Tau Protein Metabolismmentioning

confidence: 99%

Nerve growth factor as a paradigm of neurotrophins related to Alzheimer's disease

Calissano

Matrone

Amadoro

2010

Developmental Neurobiology

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“…(4) The PHFs bundle together and form neurofibrillary tangles that obstruct the cell interior. 27 ditional sites are targeted by different kinases, including cAMP-dependent protein kinase (PKA), protein kinase C (PKC), calcium/calmodulin dependent protein kinase II (CaMKII), serum-and glucocorticoid-inducible kinase (SGK), protein kinase B (PKB), microtubule-affinity regulating kinase (MARK), and SAD kinase (SADK). 76 The KIGS or KCGS motifs in the repeat domain (S262, S293, S324, S356) can be phosphorylated by MARK, PKA, PKB, SADK, CaMKII, and p70S6K.…”

Section: Antiphosphorylation Strategiesmentioning

confidence: 99%

“…In tissue culture, phosphorylation of tau repeats resulted in transport impairment, and deficits in fast anterograde transport were described in tau transgenic mice. 27,220 One major advantage of microtubule-stabilizing strategies is the availability of approved and well-established chemotherapeutic drugs such as taxol. Taxol and its derivative taxane analog TX67 stabilize microtubules and promote tubulin polymerization.…”

Section: Microtubule-stabilizing Drugsmentioning

confidence: 99%

Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

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Summary:Neurofibrillary tangles are a characteristic hallmark of Alzheimer's and other neurodegenerative diseases, such as Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). These diseases are summarized as tauopathies, because neurofibrillary tangles are composed of intracellular aggregates of the microtubule-associated protein tau. The molecular mechanisms of tau-mediated neurotoxicity are not well understood; however, pathologic hyperphosphorylation and aggregation of tau play a central role in neurodegeneration and neuronal dysfunction. The present review, therefore, focuses on therapeutic approaches that aim to inhibit tau phosphorylation and aggregation or to dissolve preexisting tau aggregates. Further experimental therapy strategies include the enhancement of tau clearance by activation of proteolytic, proteasomal, or autophagosomal degradation pathways or anti-tau directed immunotherapy. Hyperphosphorylated tau does not bind microtubules, leading to microtubule instability and transport impairment. Pharmacological stabilization of microtubule networks might counteract this effect. In several tauopathies there is a shift toward four-repeat tau isoforms, and interference with the splicing machinery to decrease four-repeat splicing might be another therapeutic option.

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“…Although the underlying mechanism connecting microtubule dynamics to axonal transport is unclear, low concentrations of taxol have been shown to compromise axonal transport (Nakata and Hirokawa, 2003). At the same time, other work suggests that increased levels of tau may interfere with axonal transport via a competition between tau and motor proteins (Trinczek et al, 1999;Stamer et al, 2002;Mandelkow et al, 2003). Another mutually nonexclusive possibility is that tau dysfunction/deregulation causes altered microtubule dynamics in glial cells, leading to glial activation, which can be cytotoxic to neurons (Bamberger and Landreth, 2002).…”

Section: How Might Tau Dysfunction Cause Neurodegeneration?mentioning

confidence: 99%

Modulation of Microtubule Dynamics by Tau in Living Cells: Implications for Development and Neurodegeneration

Bunker

Wilson

Jordan

et al. 2004

MBoC

134

127

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The neural microtubule-associated protein tau binds to and stabilizes microtubules. Because of alternative mRNA splicing, tau is expressed with either 3 or 4 C-terminal repeats. Two observations indicate that differences between these tau isoforms are functionally important. First, the pattern of tau isoform expression is tightly regulated during development. Second, mutation-induced changes in tau RNA splicing cause neuronal cell death and dementia simply by altering the isoform expression ratio. To investigate whether 3-and 4-repeat tau differentially regulate microtubule behavior in cells, we microinjected physiological levels of these two isoforms into EGFP-tubulin-expressing cultured MCF7 cells and measured the effects on the dynamic instability behavior of individual microtubules by time-lapse microscopy. Both isoforms suppressed microtubule dynamics, though to different extents. Specifically, 4-repeat tau reduced the rate and extent of both growing and shortening events. In contrast, 3-repeat tau stabilized most dynamic parameters about threefold less potently than 4-repeat tau and had only a minimal ability to suppress shortening events. These differences provide a mechanistic rationale for the developmental shift in tau isoform expression and are consistent with a loss-of-function model in which abnormal tau isoform expression results in the inability to properly regulate microtubule dynamics, leading to neuronal cell death and dementia. INTRODUCTIONThe microtubule-associated protein tau promotes neuronal cell polarization and axonal outgrowth; it is also necessary for maintaining axonal morphology and axonal transport (Caceres and Kosik, 1990;Esmaeli-Azad et al., 1994;Trinczek et al., 1999;Stamer et al., 2002). Alternatively, abnormal tau is the major component of neurofibrillary tangles, hallmark pathological features of Alzheimer's disease and related dementias.Mechanistically, tau acts by binding to microtubules directly and regulating their growing, shortening, and treadmilling dynamics (Drechsel et al., 1992;Panda et al., 1995Panda et al., , 1999Trinczek et al., 1995). Because tight regulation of microtubule dynamics and microtubule behavior can be critical to cell viability (Jordan et al., 1996;Goncalves et al., 2001), fine regulation of tau activity may be equally critical.Tau activity is regulated in part by alternative mRNA splicing, which leads to the expression of two families of tau isoforms, those containing four C-terminal repeats and those with three such repeats ( Figure 1A; Lee et al., 1988;Himmler, 1989). In vitro studies have shown that 4-repeat tau binds to, assembles, and stabilizes microtubules more effectively than 3-repeat tau (Butner and Kirschner, 1991;Gustke et al., 1994;Trinczek et al., 1995;Goode et al., 2000;Panda et al., 2003). However, there are limited data assessing the abilities of 3-or 4-repeat tau to modulate dynamics in a complex cellular environment.The importance of functional differences between 3-and 4-repeat tau is highlighted by two observations. First, altho...

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Clogging of axons by tau, inhibition of axonal traffic and starvation of synapses

Cited by 356 publications

References 37 publications

Nerve growth factor as a paradigm of neurotrophins related to Alzheimer's disease

Nerve growth factor as a paradigm of neurotrophins related to Alzheimer's disease

Tau-Based Treatment Strategies in Neurodegenerative Diseases

Modulation of Microtubule Dynamics by Tau in Living Cells: Implications for Development and Neurodegeneration

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