Tau Phosphorylation by cdk5 and Fyn in Response to Amyloid Peptide Aβ25–35: Involvement of Lipid Rafts

Hernández, Paula; Lee, Gloria; Sjöberg, Marcela; Maccioni, Ricardo B.

doi:10.3233/jad-2009-0933

Cited by 83 publications

(72 citation statements)

References 46 publications

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“…The CP17-reactive Tau was most likely located in the lipid raft fraction of the cells because solubilization of the cells for the immunoprecipitation required the use of a stringent buffer to recover all of the Tau; solubilization with 1% Triton X-100 resulted in much of the NGF-induced Tau pelleting before the immunoprecipitation (data not shown). Lipid raft-associated Tau has been previously reported (43)(44)(45)(46). These data suggested a novel function for Thr-231-phosphorylated Tau in response to NGF.…”

Section: Effects Of Tau Phosphorylation On Its Ability To Potentiatementioning

confidence: 55%

“…4), make it less likely that the effect of Tau on AP-1 transcription factors was taking place in the nucleus. Tau phosphorylated at Thr-231 may reside in lipid rafts at the plasma membrane, as has been previously reported for Tau phosphorylated at Ser-396/Ser-404 (43)(44)(45)(46). Lipid rafts have established importance in signal transduction (reviewed by Refs.…”

Section: Discussionmentioning

confidence: 69%

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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: Effects Of Tau Phosphorylation On Its Ability To Potentiatementioning

confidence: 55%

Section: Discussionmentioning

confidence: 69%

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 NR2B/PSD-95/Fyn complex that is formed when NMDA receptors are activated perpetuates Ca 2+ influx, which can activate 2 key tau kinases, GSK-3β 175 and CDK5. 176 It is therefore possible that NMDA receptor activation stabilizes the NR2B/PSD-95/Fyn complex, resulting in a persistent activation of the NMDA receptor channel and increasing tau phosphorylation either by direct phosphorylation of tau via Fyn kinase or by activating other tau kinases, such as GSK-3β or CDK5. 177 It is also of interest to note that tau is required for the transportation of Fyn kinase to the postsynapse, where it forms a complex with PSD-95 and the NR2B subunit of the NMDA receptor.…”

Section: Glutamate and Amyloid β-Mediated Tau Phosphorylationmentioning

confidence: 99%

Glutamate system, amyloid β peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology

Revett

Baker

Jhamandas³

et al. 2013

J Psychiatry Neurosci

256

182

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“…Unfortunately, our knowledge of the many biochemical events upstream and downstream of Tau remains poorly understood. It is known, however, that A␤ induces increased activity of several Tau-targeting kinases, including GSK3␤ and Cdk5 (13,14). Additionally, hyperphosphorylated Tau has been shown to possess a reduced ability to bind and regulate microtubule behavior (15) while harboring an increased propensity to aggregate (16).…”

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confidence: 99%

Amyloid β-Mediated Cell Death of Cultured Hippocampal Neurons Reveals Extensive Tau Fragmentation without Increased Full-length Tau Phosphorylation

Reifert¹,

Hartung-Cranston²,

Feinstein

2011

Journal of Biological Chemistry

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A variety of genetic and biochemical evidence suggests that amyloid ␤ (A␤) oligomers promote downstream errors in Tau action, in turn inducing neuronal dysfunction and cell death in Alzheimer and related dementias. To better understand molecular mechanisms involved in A␤-mediated neuronal cell death, we have treated primary rat hippocampal cultures with A␤ oligomers and examined the resulting cellular changes occurring before and during the induction of cell death with a focus on altered Tau biochemistry. The most rapid neuronal responses upon A␤ administration are activation of caspase 3/7 and calpain proteases. A␤ also appears to reduce Akt and Erk1/2 kinase activities while increasing GSK3␤ and Cdk5 activities. Shortly thereafter, substantial Tau degradation begins, generating relatively stable Tau fragments. Only a very small fraction of fulllength Tau remains intact after 4 h of A␤ treatment. In conflict with expectations based on suggested increases of GSK3␤ and Cdk5 activities, A␤ does not cause any major increases in phosphorylation of full-length Tau as assayed by immunoblotting one-dimensional gels with 11 independent site-and phosphospecific anti-Tau antibodies as well as by immunoblotting twodimensional gels probed with a pan-Tau antibody. There are, however, subtle and transient increases in Tau phosphorylation at 3-4 specific sites before its degradation. Taken together, these data are consistent with the notion that A␤-mediated neuronal cell death involves the loss of full-length Tau and/or the generation of toxic fragments but does not involve or require hyperphosphorylation of full-length Tau.Many neurodegenerative diseases are characterized by the accumulation of aggregated proteins in the brain. For example, the microtubule-associated protein Tau forms aggregates in a variety of neurodegenerative diseases known as tauopathies, including Alzheimer, frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy, corticobasal degeneration, and related dementias (1, 2). Alzheimer disease is distinguished from many other tauopathies by accumulation of a second pathological feature known as amyloid ␤ (A␤) 3 plaques (3, 4). Complementary genetic evidence demonstrates that errors in the action or regulation of either Tau or the amyloid precursor protein (which is proteolytically cleaved to produce A␤) can cause neuronal cell death and dementia in humans (5). Furthermore, experiments in both cultured rodent hippocampal neurons and transgenic mice demonstrate that A␤-mediated neuronal cell death and memory deficits require Tau (6, 7). Taken together, the data suggest an intrinsic relationship between A␤ and Tau dysfunction. Indeed, the widely cited "amyloid cascade hypothesis" proposes that A␤ oligomers induce aberrant effects on Tau, which in turn promotes neurodegeneration and dementia (8 -10).One central feature of Alzheimer and related dementias is that Tau isolated from affected brains is hyperphosphorylated (11,12). This observation led investigators to ...

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Tau Phosphorylation by cdk5 and Fyn in Response to Amyloid Peptide Aβ25–35: Involvement of Lipid Rafts

Cited by 83 publications

References 46 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

Glutamate system, amyloid β peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology

Amyloid β-Mediated Cell Death of Cultured Hippocampal Neurons Reveals Extensive Tau Fragmentation without Increased Full-length Tau Phosphorylation

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