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Cell Cycle Hypothesis Pedaling into Mainstream Acceptance? Results in Fly, Mouse Models Warrant a Second Look
 View Transcript of Live Discussion — Posted 12 April 2006
View Comments By:
Jin-Jing Pei — Posted 3 March 2006
Agata Copani — Posted 6 March 2006
John Staropoli — Posted 6 March 2006
Zsuzsanna Nagy — Posted 7 March 2006
Background Text
In 2002, the Alzforum hosted a Live Discussion led by Inez Vincent. She and a few other scientists had developed the hypothesis that aberrant reactivation of the cell cycle might cause neurodegeneration and constitute an early event in the pathogenesis of Alzheimer disease, because postmitotic neurons that reawaken their cell cycle tend not to divide, but die. At the time, the idea languished in relative obscurity, and the discussion concluded with a consensus that the field needed to move its observations from postmortem human tissue and cell culture into in-vivo studies. Above all, tests in animal models were needed next.
Three years later, those data have begun coming in, and it is time to catch up with the progress and reevaluate the hypothesis in light of it. Below is a brief synopsis of Khurana et al. (Khurana at al., 2006), as well as another recent paper, a collaborative effort by Herrup and Bruce Lamb to assess cell cycle reactivation in a suite of APP transgenic mouse models. An earlier paper by Cathy Andorfer, Karen Duff, Peter Davies and colleagues had set the stage by demonstrating cell-cycle reactivation in a mouse neurodegeneration model of normal human tau (see Andorfer et al., 2005 and commentary there).
Khurana and colleagues picked up the hypothesis roughly where it had led off after the last discussion: Aberrant expression and mislocalization of numerous cell-cycle proteins had been shown in neurons of postmortem AD and tauopathy tissues, and Herrup’s lab added the observation that neurons in AD tissue actually replicate their DNA before dying. The open questions were whether this was a cause of neurodegeneration or an epiphenomenon to it, and which signaling pathways might be turning on the cell cycle. How, in other words, did it fit in with established players in AD, such as APP and tau? A number of mitogenic pathways were known to be up-regulated in AD, including the one involving TOR that Khurana would focus on in his study. And yet, many different kinds of signaling pathways are changed in AD, and the relevance of the mitogenic up-regulation to the disease process was far from clear.
Khurana and Feany approached these questions from an existing interest in tauopathies. Consequences of tau hyperphosphorylation are seen as a common effector of neurodegeneration in several different diseases. If tau-induced degeneration and cell cycle activation are indeed linked, they asked, how so and what causes what?
In the present study, the researchers used Drosophila models of wild-type and mutant tau. Fruit flies not only recapitulate the basic cell cycle machinery and key features of tau-induced neurodegeneration, but also, the relative ease with which one can manipulate flies genetically and pharmacologically allowed the scientists to address the question of causation. Conveniently, flies express the mitogenic pathway involving target of rapamycin (TOR) kinase, which Seymour Benzer’s group had shown to affect lifespan and Jin Jing Pei’s group had shown to be altered in AD tissue.
Khurana et al. demonstrated a series of events whereby tau phosphorylation activated the cell cycle, and that immediately preceded neurodegeneration by apoptosis. Blocking various cell cycle transition points blocked apoptosis, even though tau pathology stayed in place. The TOR pathway drove tau-induced cell cycle activation. The sequence of events, then, in this animal model is: Tau —TOR pathway—cell cycle—neuron death. New in this study are the findings that cell cycle activation causes neuron death, and that cell cycle activation is downstream from tau phosphorylation, not the other way around. The paper supports previous cell culture studies that had shown cell cycle-dependent apoptosis in a number of neurotoxicity assays.
Many questions remain. For one, the mechanism of cell death remains puzzling. Khurana et al. saw apoptosis but do not rule out other mechanisms. An important prior study of tau-induced neurodegeneration in mice, by Andorfer and colleagues, also strongly pointed to cell cycle activation but saw apoptotic as well as non-apoptotic degeneration. On this issue, a new study appearing in Neuron on 2 March, by Azad Bonni and colleagues at Harvard Medical School, suggests that neurons have unique intracellular signaling systems regulating cell death. It further implicates the prolyl isomerase P1, which is already known to counteract the damaging effects of tau hyperphosphorylation, in this process (Becker et al., 2006, in press). Bonni has published previously on cell cycle, cell death, and neurodegeneration (Becker et al., 2004 and comment there).
For another question, there remains uncertainty about whether cell cycle activation is a universal mechanism across many forms of neurodegeneration, or whether it is specific to tauopathies including AD. Previous papers have reported discrepant data on cell cycle activation in diseases such as ALS, Parkinson and Huntington diseases, ataxias, or stroke and trauma. For their part, Khurana and colleagues did not find TOR/cell cycle activation in fly models of Parkinson or polyglutamine disease. They favor the notion that mechanisms of neurodegeneration in different diseases are quite distinct.
In closing, Khurana et al. write that cancer and tauopathies share a common effector pathway in TOR, and suggest TOR and cell cycle inhibitors might make therapeutic targets in tauopathies and AD.
Another new paper on the topic of the cell cycle and AD came this January from Yan Yang and Nicholas Varvel, working with Bruce Lamb and Karl Herrup at Case Western Reserve University in Cleveland, Ohio (Yang et al., 2006; see commentary by Inez Vincent there). These scientists assessed what they call ectopic cell cycle events in four different strains of APP-transgenic mice. In addition to well-known models such as the Tg2576 mouse, this included a model made by Lamb that expresses full-length genomic APP driven by the human APP promoter. The scientists found that all four models show ectopic cell cycle events, that is, expression of cell cycle regulators and DNA replication, months before either amyloid deposition or inflammation. Confirming earlier in-vitro work by Donna McPhie and Rachael Neve, these findings indicate that cell cycle activation is an early expression of neural distress, not merely one of numerous later consequences of the AD process. The paper suggests that APP-transgenic mice are actually more faithful models than is sometimes said, Yang et al. write, because with the cell cycle activation, they recapitulate yet another sign of early human AD, and they do so in a temporal and spatial pattern that closely tracks human disease progression.
Curiously, Yang et al. in this study repeated an observation they had made in their earlier work. Neurons that have attempted to replicate their DNA, that is, moved part of the way through the cell cycle, did not die soon thereafter, as they did in Khurana’s tau model, but instead lingered on for months. Clearly something is still missing to produce neuron loss, and a “complete” mouse model of AD. Oxidative stress (Zhu et al., 2004) and tau hyperphosphorylation (Andorfer et al., 2005) are obvious candidates. Clearly, both the tau and amyloid branches of AD pathologies have links to the cell cycle in animal models.—Gabrielle Strobel.
References:
Andorfer C, Acker CM, Kress Y, Hof PR, Duff K, Davies P. Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J Neurosci. 2005 Jun 1;25(22):5446-54. Abstract
Neve RL, McPhie DL. The cell cycle as a therapeutic target for Alzheimer's disease. Pharmacol Ther. 2005 Nov 7. Abstract
McPhie DL, Coopersmith R, Hines-Peralta A, Chen Y, Ivins KJ, Manly SP, Kozlowski MR, Neve KA, Neve RL. DNA synthesis and neuronal apoptosis caused by familial Alzheimer disease mutants of the amyloid precursor protein are mediated by the p21 activated kinase PAK3. J Neurosci. 2003 Jul 30;23(17):6914-27. Abstract
Neve RL, McPhie DL, Chen Y. Alzheimer's disease: dysfunction of a signalling pathway mediated by the amyloid precursor protein? Biochem Soc Symp. 2001 ;:37-50. Abstract
Staropoli JF, Abeliovich A. The ubiquitin-proteasome pathway is necessary for maintenance of the postmitotic status of neurons. J Mol Neurosci. 2005 ;27(2):175-83. Abstract
Aulia S, Tang BL. Cdh1-APC/C, cyclin B-Cdc2, and Alzheimer's disease pathology. Biochem Biophys Res Commun. 2006 Jan 6;339(1):1-6. Abstract
Webber KM, Casadesus G, Zhu X, Obrenovich ME, Atwood CS, Perry G, Bowen RL, Smith MA. The cell cycle and hormonal fluxes in Alzheimer disease: a novel therapeutic target. Curr Pharm Des. 2006 ;12(6):691-7. Abstract
Anekonda TS, Reddy PH. Neuronal protection by sirtuins in Alzheimer's disease. J Neurochem. 2006 Jan ;96(2):305-13. Abstract
Lu KP, Liou YC, Vincent I. Proline-directed phosphorylation and isomerization in mitotic regulation and in Alzheimer's Disease. Bioessays. 2003 Feb ;25(2):174-81.
Abstract
Vincent I, Pae CI, Hallows JL. The cell cycle and human neurodegenerative disease. Prog Cell Cycle Res. 2003 ;5():31-41. Abstract
Yang Y, Herrup K. Loss of neuronal cell cycle control in ataxia-telangiectasia: a unified disease mechanism. J Neurosci. 2005 Mar 9;25(10):2522-9. Abstract
Yang Y, Mufson EJ, Herrup K. Neuronal cell death is preceded by cell cycle events at all stages of Alzheimer's disease. J Neurosci. 2003 Apr 1;23(7):2557-63. Abstract
Becker EB, Bonni A. Pin1 mediates neural-specific activation of the mitochondrial apoptotic machinery. Neuron. 2006 Mar 2;49(5):655-62. Abstract
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Comments on Live Discussion |
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Comment by: Jin-Jing Pei
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Submitted 3 March 2006
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Posted 3 March 2006
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In AD brain, total tau is markedly increased in the hyperphosphorylated form, and a significant amount of normal tau still exists. Although the tau mRNA level is increased in the brains of Down syndrome patients, it is not changed in AD brains, and thus the role of increased tau synthesis has mostly been neglected.
In neurons of AD brains, we have found up-regulation of the rapamycin-dependent protein translation pathway including mammalian target of rapamycin (mTOR) and p70 S6 kinase (p70S6K), which targets a group of mRNAs having 5’-terminal oligopyrimidine tracts such as tau mRNA. We have further shown that manipulation of p70S6K activity by selective PP-2A inhibition in cultured rat brain slices and zinc treatment in SH-SY5Y neuroblastoma cells and primary hippocampal neurons results in corresponding changes of tau level, as well as phosphorylation at Ser262, Thr212, and Ser214 that can prevent tau from binding to microtubules.
Our recent data indicate that deregulation of mTOR/p70S6K signaling might play a dual role in accumulation of hyperphosphorylated tau by...
Read more
In AD brain, total tau is markedly increased in the hyperphosphorylated form, and a significant amount of normal tau still exists. Although the tau mRNA level is increased in the brains of Down syndrome patients, it is not changed in AD brains, and thus the role of increased tau synthesis has mostly been neglected.
In neurons of AD brains, we have found up-regulation of the rapamycin-dependent protein translation pathway including mammalian target of rapamycin (mTOR) and p70 S6 kinase (p70S6K), which targets a group of mRNAs having 5’-terminal oligopyrimidine tracts such as tau mRNA. We have further shown that manipulation of p70S6K activity by selective PP-2A inhibition in cultured rat brain slices and zinc treatment in SH-SY5Y neuroblastoma cells and primary hippocampal neurons results in corresponding changes of tau level, as well as phosphorylation at Ser262, Thr212, and Ser214 that can prevent tau from binding to microtubules.
Our recent data indicate that deregulation of mTOR/p70S6K signaling might play a dual role in accumulation of hyperphosphorylated tau by increasing tau synthesis as well as tau phosphorylation. Our observations thus indicate that apart from hyperphosphorylation of tau, increased synthesis of novel tau might be a primary event in neurodegeneration, leading to formation of tau tangle in neurons. Taken together with the evidence that activities of mTOR and p70S6K are localized to NFT-bearing neurons, and significantly correlated with total tau levels in AD brains, we hypothesize that deregulated mTOR/p70S6K signaling plays a causative role in the accumulation of abnormally hyperphosphorylated tau in the AD brain.
References:
1. Pei JJ, Gong CX, An WL, Winblad B, Cowburn RF, Grundke-Iqbal I, Iqbal K. Okadaic-acid-induced inhibition of protein phosphatase 2A produces activation of mitogen-activated protein kinases ERK1/2, MEK1/2, and p70 S6, similar to that in Alzheimer's disease.
Am J Pathol. 2003 Sep;163(3):845-58.
Abstract
2. Pei JJ, Khatoon S, An WL, Nordlinder M, Tanaka T, Braak H, Tsujio I, Takeda M, Alafuzoff I, Winblad B, Cowburn RF, Grundke-Iqbal I, Iqbal K. Role of protein kinase B in Alzheimer's neurofibrillary pathology.
Acta Neuropathol (Berl). 2003 Apr;105(4):381-92. Epub 2002 Dec 18.
Abstract
3. An WL, Cowburn RF, Li L, Braak H, Alafuzoff I, Iqbal K, Iqbal IG, Winblad B, Pei JJ. Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer's disease.
Am J Pathol. 2003 Aug;163(2):591-607. Erratum in: Am J Pathol. 2003 Dec;163(6):2645.
Abstract
4. An WL, Bjorkdahl C, Liu R, Cowburn RF, Winblad B, Pei JJ. Mechanism of zinc-induced phosphorylation of p70 S6 kinase and glycogen synthase kinase 3beta in SH-SY5Y neuroblastoma cells.
J Neurochem. 2005 Mar;92(5):1104-15.
Abstract
5. An WL, Pei JJ, Nishimura T, Winblad B, Cowburn RF. Zinc-induced anti-apoptotic effects in SH-SY5Y neuroblastoma cells via the extracellular signal-regulated kinase 1/2.
Brain Res Mol Brain Res. 2005 Apr 27;135(1-2):40-7. Epub 2005 Jan 8.
Abstract
6. Bjorkdahl C, Sjogren MJ, Winblad B, Pei JJ. Zinc induces neurofilament phosphorylation independent of p70 S6 kinase in N2a cells.
Neuroreport. 2005 Apr 25;16(6):591-5.
Abstract
7. Li X, Alafuzoff I, Soininen H, Winblad B, Pei JJ. Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain.
FEBS J. 2005 Aug;272(16):4211-20.
Abstract
8. Pei JJ, An WL, Zhou XW, Nishimura T, Norberg J, Benedikz E, Gotz J, Winblad B. P70 S6 kinase mediates tau phosphorylation and synthesis.
FEBS Lett. 2006 Jan 9;580(1):107-14. Epub 2005 Dec 6.
Abstract
View all comments by Jin-Jing Pei |
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Comment by: Agata Copani
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Submitted 6 March 2006
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Posted 6 March 2006
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Surely, the paper by Khurana et al. supports the hypothesis that cell cycle reactivation in postmitotic neurons leads to death. In particular, the paper shows that
1. tau-induced neurodegeneration in Drosophila is partially prevented by cell cycle blockade;
2. ectopic cell cycle activation, in the absence of transgenic tau, leads to neuronal apoptosis (even though this is not always the case: see Fig. 4H vs. Fig. 2C) and enhances tau-induced toxicity;
3. the inhibition of endogenous TOR activity partly suppresses tau-induced neurodegeneration, whereas ectopic TOR activation induces cell cycle activation and neurodegeneration;
4. TOR activation enhances tau-induced toxicity, and this enhancement is blocked by concomitant cell cycle inhibition.
The conclusion is that the TOR pathway drives tau-induced cell cycle activation with ensuing neurodegeneration. However, this conclusion suffers from the lack of direct evidence that the inhibition of endogenous TOR activity prevents tau-activated cell cycle activation besides neurodegeneration. Otherwise, it...
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Surely, the paper by Khurana et al. supports the hypothesis that cell cycle reactivation in postmitotic neurons leads to death. In particular, the paper shows that
1. tau-induced neurodegeneration in Drosophila is partially prevented by cell cycle blockade;
2. ectopic cell cycle activation, in the absence of transgenic tau, leads to neuronal apoptosis (even though this is not always the case: see Fig. 4H vs. Fig. 2C) and enhances tau-induced toxicity;
3. the inhibition of endogenous TOR activity partly suppresses tau-induced neurodegeneration, whereas ectopic TOR activation induces cell cycle activation and neurodegeneration;
4. TOR activation enhances tau-induced toxicity, and this enhancement is blocked by concomitant cell cycle inhibition.
The conclusion is that the TOR pathway drives tau-induced cell cycle activation with ensuing neurodegeneration. However, this conclusion suffers from the lack of direct evidence that the inhibition of endogenous TOR activity prevents tau-activated cell cycle activation besides neurodegeneration. Otherwise, it could be argued that TOR activation is responsible for cell cycle events that enhance tau toxicity but are not necessarily downstream to tau.
The other main conclusion of the paper is that cell cycle activation does not invariably lead to neuronal apoptosis. The authors show that there is no evidence of cell cycle activation in the fly models of Machado Joseph disease and Parkinson disease. This is a very interesting observation suggesting that cell cycle activation may be specific to tauopathies. However, in several brain diseases, cell cycle signaling might be mandatory only when other mechanisms are not enough for neurons to reach the threshold for death (Copani et al., 2001), whereas it might happen that the forced expression of a protein in an animal model becomes sufficient to trigger apoptosis independently of cell cycle activation.
View all comments by Agata Copani |
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Comment by: John Staropoli
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Submitted 5 March 2006
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Posted 6 March 2006
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I regret that I won’t be able to join the live discussion, but I have offered the following as possible points of discussion:
The paper by Khurana et al. continues the long arc of genetic studies suggesting that cell-cycle reactivation in neurons precedes, or at least is coincident with, neuronal apoptosis.
Here are some additional experiments to consider: In an experiment analogous to the ectopic expression of cyclin E and E2F1/DP in the Khurana paper, mice transgenic for the SV40 T antigen show disrupted cerebellar cortical development and progressive degeneration of Purkinje neurons (1). The harlequin mouse, a naturally occurring strain with a proviral insertion in the gene for apoptosis-inducing factor (AIF), shows specific degeneration of retinal ganglion cells and cerebellar Purkinje cells. By a mechanism that remains unclear, AIF deficiency renders these cells more sensitive to reactive oxygen species, and dying neurons appear to show signs of oxidative damage, such as 8-OhdG immunoreactivity, before upregulation of the S phase markers PCNA and Cdc47 and the...
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I regret that I won’t be able to join the live discussion, but I have offered the following as possible points of discussion:
The paper by Khurana et al. continues the long arc of genetic studies suggesting that cell-cycle reactivation in neurons precedes, or at least is coincident with, neuronal apoptosis.
Here are some additional experiments to consider: In an experiment analogous to the ectopic expression of cyclin E and E2F1/DP in the Khurana paper, mice transgenic for the SV40 T antigen show disrupted cerebellar cortical development and progressive degeneration of Purkinje neurons (1). The harlequin mouse, a naturally occurring strain with a proviral insertion in the gene for apoptosis-inducing factor (AIF), shows specific degeneration of retinal ganglion cells and cerebellar Purkinje cells. By a mechanism that remains unclear, AIF deficiency renders these cells more sensitive to reactive oxygen species, and dying neurons appear to show signs of oxidative damage, such as 8-OhdG immunoreactivity, before upregulation of the S phase markers PCNA and Cdc47 and the apoptotic marker cleaved caspase-3 (2).
Clinical evidence for the association between unscheduled mitotic activity and neuronal apoptosis includes the detection, by fluorescence in situ hybridization, of replicated DNA at certain chromosomal loci in affected hippocampal neurons from AD patients (3). Kruman et al. elegantly demonstrated that de novo DNA synthesis is not simply an epiphenomenon or nonspecific correlate of neuronal apoptosis (4).
There are likely to be several pathways in addition to TOR signaling that mediate cell cycle activation in neuronal subtypes. Our own recent work using primary cultures of murine midbrain neurons shows that the ubiquitin-proteasome pathway UPP is required to maintain the postmitotic status of neurons and that downregulation of certain components of the UPP, such as cullin-1, cause relatively specific loss of dopaminergic neurons (5). (I would be happy to provide a PDF attachment of the paper for anyone interested.) The approximate counterpart to this study in primary cortical neurons is offered by Almeida et al. (6-8)
References:
1. Feddersen RM, Ehlenfeldt R, Yunis WS, Clark HB, Orr HT. Disrupted cerebellar cortical development and progressive degeneration of Purkinje cells in SV40 T antigen transgenic mice.
Neuron. 1992 Nov;9(5):955-66.
1419002
2. Klein JA, Longo-Guess CM, Rossmann MP, Seburn KL, Hurd RE, Frankel WN, Bronson RT, Ackerman SL. The harlequin mouse mutation downregulates apoptosis-inducing factor.
Nature. 2002 Sep 26;419(6905):367-74.
12353028
3. Yang Y, Geldmacher DS, Herrup K. DNA replication precedes neuronal cell death in Alzheimer's disease.
J Neurosci. 2001 Apr 15;21(8):2661-8.
11306619
4. Kruman II, Wersto RP, Cardozo-Pelaez F, Smilenov L, Chan SL, Chrest FJ, Emokpae R Jr, Gorospe M, Mattson MP. Cell cycle activation linked to neuronal cell death initiated by DNA damage.
Neuron. 2004 Feb 19;41(4):549-61.
14980204
5. Staropoli JF, Abeliovich A. The ubiquitin-proteasome pathway is necessary for maintenance of the postmitotic status of neurons.
J Mol Neurosci. 2005;27(2):175-83.
16186628
6. Aulia S, Tang BL. Cdh1-APC/C, cyclin B-Cdc2, and Alzheimer's disease pathology.
Biochem Biophys Res Commun. 2006 Jan 6;339(1):1-6. Epub 2005 Oct 21. Review.
16253208
7. Stegmuller J, Bonni A. Moving past proliferation: new roles for Cdh1-APC in postmitotic neurons.
Trends Neurosci. 2005 Nov;28(11):596-601. Epub 2005 Sep 15. Review.
16168498
8. Almeida A, Bolanos JP, Moreno S. Cdh1/Hct1-APC is essential for the survival of postmitotic neurons.
J Neurosci. 2005 Sep 7;25(36):8115-21.
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View all comments by John Staropoli |
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Comment by: Zsuzsanna Nagy
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Submitted 6 March 2006
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Posted 7 March 2006
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The paper by Khurana is an elegant extension of previous studies on the consequences of tau overexpression in neurons (1-3). Previous studies have shown that overexpression of normal human tau (and an imbalance between the 3R/4R tau) in the mouse brain leads to the reactivation of the cell cycle in neurons (1). They have also found that this cell cycle reactivation can lead to neuronal death in their transgenic animals. Almost concomitantly, it has been demonstrated that the overexpression of tau in Drosophila neurons alters synaptic plasticity and neurotransmission (2,3).
This study by Khurana goes one step further: It demonstrates that the cell cycle activation in response to tau overexpression (normal or mutated) is mediated by the activation of mTOR (target of rapamycin). The study has important implications.
In contrast with previous studies (4), it proves that in some tauopathies associated with tau mutations, neuronal death might be executed via the activation of the cell cycle. As such, it brings the cell cycle closer to acceptance by the neuroscience...
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The paper by Khurana is an elegant extension of previous studies on the consequences of tau overexpression in neurons (1-3). Previous studies have shown that overexpression of normal human tau (and an imbalance between the 3R/4R tau) in the mouse brain leads to the reactivation of the cell cycle in neurons (1). They have also found that this cell cycle reactivation can lead to neuronal death in their transgenic animals. Almost concomitantly, it has been demonstrated that the overexpression of tau in Drosophila neurons alters synaptic plasticity and neurotransmission (2,3).
This study by Khurana goes one step further: It demonstrates that the cell cycle activation in response to tau overexpression (normal or mutated) is mediated by the activation of mTOR (target of rapamycin). The study has important implications.
In contrast with previous studies (4), it proves that in some tauopathies associated with tau mutations, neuronal death might be executed via the activation of the cell cycle. As such, it brings the cell cycle closer to acceptance by the neuroscience community, which 10 year ago cringed even at the mention of the cell cycle.
It also identifies mTOR as the possible molecular link between altered synaptic plasticity and the activation of cell cycle in neurons, providing one more element of the morphodysregulation scenario proposed by Arendt for the pathogenesis of Alzheimer disease (5).
The upregulation of mTOR in AD brains has been found in association with cell cycle activation (6,7) and the accumulation of PHF tau. The present paper confirms in a transgenic model the possible role of mTOR in the pathogenesis of Alzheimer disease. It also shows that the inhibition of the cell cycle can rescue neurons from death in this model.
But does this Drosophila model prove that tau accumulation is the primary event and the cell cycle activation a secondary phenomenon in sporadic Alzheimer disease?
In sporadic AD, the expression of tau is not upregulated (8) and there are no tau mutations. The upregulation of mTOR and the cell cycle activation in neurons occurs independently of tau overexpression. Additionally, lymphocytes from Alzheimer patients show reduced responsiveness to rapamycin (9), indicating the either mTOR or its downstream effectors (10) are altered in many cells (not just neurons) in Alzheimer disease patients.
Although I think that it would be premature to draw too many conclusions regarding the pathogenesis of sporadic Alzheimer disease based on this Drosophila model, it certainly provides a valuable tool for studying the relationship among cell cycle activation, tau, and neuronal dysfunction. It is a beautiful and thorough study. I am just sorry I shall not be able to participate in the discussion today.
References:
1. Andorfer C, Acker CM, Kress Y, Hof PR, Duff K, Davies P, Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J Neurosci, 2005. 25(22): p. 5446-54. Abstract
2. Chee F, Mudher A, Newman TA, Cuttle M, Lovestone S, Shepherd D, Overexpression of tau results in defective synaptic transmission in Drosophila neuromuscular junctions. Biochem Soc Trans, 2006. 34(Pt 1): p. 88-90. Abstract
3. Chee FC, Mudher A, Cuttle MF, Newman TA, MacKay D, Lovestone S, Shepherd D, Over-expression of tau results in defective synaptic transmission in Drosophila neuromuscular junctions. Neurobiol Dis, 2005. 20(3): p. 918-28. Abstract
4. Delobel P, Lavenir I, Ghetti B, Holzer M, Goedert M, Cell-Cycle Markers in a Transgenic Mouse Model of Human Tauopathy: Increased Levels of Cyclin-Dependent Kinase Inhibitors p21Cip1 and p27Kip1. Am J Pathol, 2006. 168(3): p. 878-87. Abstract
5. Arendt T, Synaptic plasticity and cell cycle activation in neurons are alternative effector pathways: the 'Dr. Jekyll and Mr. Hyde concept' of Alzheimer's disease or the yin and yang of neuroplasticity. Prog Neurobiol, 2003. 71(2-3): p. 83-248. Abstract
6. An WL, Cowburn RF, Li L, Braak H, Alafuzoff I, Iqbal K, Iqbal IG, Winblad B, Pei JJ, Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer's disease. Am J Pathol, 2003. 163(2): p. 591-607. Abstract
7. Li X, Alafuzoff I, Soininen H, Winblad B, Pei JJ, Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain. Febs J, 2005. 272(16): p. 4211-20. Abstract
8. Connell JW, Rodriguez-Martin T, Gibb GM, Kahn NM, Grierson AJ, Hanger DP, Revesz T, Lantos PL, Anderton BH, Gallo JM, Quantitative analysis of tau isoform transcripts in sporadic tauopathies. Brain Res Mol Brain Res, 2005. 137(1-2): p. 104-9. Abstract
9. Nagy Z, Combrinck M, Budge M, McShane R, Cell cycle kinesis in lymphocytes in the diagnosis of Alzheimer's disease. Neurosci Lett, 2002. 317(2): p. 81-4. Abstract
10. Hay N, Sonenberg N, Upstream and downstream of mTOR. Genes Dev, 2004. 18(16): p. 1926-45. Abstract
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