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Curbing Cell Cycle Re-entry: Window of Opportunity for NSAIDs?
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Updated 2 December 2009
24 November 2009. The aberrant re-entry of post-mitotic neurons into the cell cycle is an early event in AD pathology, preceding amyloid deposition and possibly putting cells in a vulnerable state for subsequent neurodegeneration. Blame it on neuroinflammation, says a new report from Karl Herrup of Rutgers University in Piscataway, New Jersey, and Bruce Lamb of the Cleveland Clinic and Case Western Reserve University in Cleveland, Ohio. Their paper, published on November 9 online in the Journal of Clinical Investigation, shows that activation of brain microglia is responsible for the appearance of cell cycle protein markers in neurons in young AD mice. Further, they find that non-steroidal anti-inflammatory drugs (NSAIDs) can prevent the appearance of these early cell cycle events. However, starting NSAID treatment after cell cycle entry has initiated cannot reverse the abnormalities. The results support the idea that NSAIDs might help prevent AD if deployed early in the disease progression, a concept that is gaining some support from recent post-hoc analysis of the stopped Alzheimer’s Disease Antiinflammatory Prevention Trial (ADAPT).
First author Nicholas Varvel, who is a joint graduate student in the Lamb and Herrup labs, looked at the induction of aberrant cell cycle entry in Lamb’s R1.40 mouse model, which expresses Swedish mutant human APP under a human promoter. The mice show amyloid deposition at 12-14 months of age, but by six months of age, neurons start to show aberrant cyclin D and A expression, which depends on γ-secretase activity and Aβ production (see ARF related news story on Varvel et al., 2008). [Editor's note: See clarification below in comment from Nicolas Varvel.]
In the new work, Varvel finds a coincident activation of microglia, which also depended on Aβ production.
To determine if the microglial activation and cell cycle events (CCEs) were causally linked, the researchers induced inflammation in two-month-old R1.40 mice, before CCEs normally appear. Injecting the mice with lipopolysaccharide resulted in microglial activation and the onset of CCEs. Varvel also looked at the effects of damping spontaneous inflammation in R1.40 mice by treating them with the NSAIDs ibuprofen or naproxen. When the mice were continuously dosed from three to six months of age, the researchers found less activation of microglia and fewer cells with aberrant cell cycle expression. Despite their documented inhibition of the amyloid-producing enzymes BACE and γ-secretase, the NSAIDs had no effect on Aβ production or the relative amounts of Aβ40 and 42, leaving the researchers to conclude that the primary effects of NSAIDs on CCEs occur at the level of microglial inflammation.
The appearance of cyclin-positive neurons is time- and location-dependent in the mice, which gave the researchers a chance to look at the question of whether NSAIDs can reverse CCEs once they have formed. Interestingly, NSAID treatment from six to 12 months had no effect on the number of early-forming CCEs, which appear in cortical layers II/III by the time the mice are six months old. However, treatment did block appearance of CCEs in the adjacent layers V/VI, where cyclin-expressing neurons normally show up later, at around 12 months of age.
It is not yet clear how the appearance of CCEs or the early or late effects of NSAIDs correlate with behavior in the mice, but the researchers are looking at that now, coauthor Lamb said.
The study may bring some clarity to the confusion over NSAIDs and AD. Retrospective epidemiological studies suggest NSAIDs offer some protection from dementia, but prospective studies have been disappointing. The ADAPT trial, a large, placebo-controlled study, was halted in 2004 for safety reasons after treated patients showed an increase in cardiovascular events (see ARF related news story). That turned out be a controversial move (see ARF related news story). The trial reported negative results in 2008, at the same time as another observational study supported the preventive effect of NSAIDs (see ARF related news story on Martin et al., 2008 and Vlad et al., 2008).
The latest look at the ADAPT data suggests there may be a window of opportunity for prevention early on in cognitively intact people. John Breitner of the University of Washington, Seattle, has been following up on the ADAPT subjects. He presented incidence and biomarker data at ICAD 2009 (see ARF related news story), and more recently at the Clinical Trials on Alzheimer’s Disease (CTAD) meeting in Las Vegas, that suggest that one to three years of treatment with naproxen may ultimately reduce the incidence of AD five to 10 years out in the people who were least affected at the time of treatment. That contrasts with the effects of the drug in the early years of the trial, where it appeared to hasten the onset of dementia in the subset of people who were further along the path to disease. At CTAD, Breitner showed that the hazard ratios for dementia in those taking the naproxen or celecoxib for over two years were 0.33 and 0.64, respectively. The apparent protection afforded by naproxen also emerged when he looked at biomarkers. Those taking naproxen over extended periods had a 40 percent reduction in the CSF total tau/Aβ42 ratio.
Breitner told ARF he finds the new study exciting and intriguing. “To be able to show that these NSAIDs have an effect at one phase of the disease development which is lost later—that’s something that I've been very interested in for a long time because we are seeing very similar things in our human experimental work with ADAPT. Any time you can find something in animals that mimics something as unexpected and unusual as that, I think it’s very interesting,” he said.
How does that mouse work relate to timing of treatment in humans? That is not clear yet, Lamb told ARF. “In the mouse we have some good ideas of when to treat, but translating that to the humans is tough,” he said. Right now, they are trying to figure out if there are biomarkers for the onset of inflammation and CCEs in the mouse that might apply to people, too. “We are now looking at inflammatory molecules within the brain, but also beginning to try to look at things in serum and CSF. If we could link this to something biological, then that might help in terms of trying to figure out when is the right time to start treatment,” he said.—Pat McCaffrey.
Reference:
Varvel NH, Bhaskar K, Kounnas MZ, Wagner SL, Yang Y, Lamb BT, Herrup K. NSAIDs prevent, but do not reverse, neuronal cell cycle reentry in a mouse model of Alzheimer disease. J Clin Invest. 2009 Nov 9. pii: 39716. doi: 10.1172/JCI39716. Abstract
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Comments on News and Primary Papers |
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Primary Papers: NSAIDs prevent, but do not reverse, neuronal cell cycle reentry in a mouse model of Alzheimer disease.
Comment by: Agata Copani
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Submitted 24 November 2009
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Posted 24 November 2009
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Evidence exists that cell death seen in AD arises from neurons attempting to divide, and this is why researchers working in the field believe that AD therapy might benefit from drugs able to arrest cell division in neurons. Until this paper by Varvel and colleagues, however, that hypothesis had not been truly tested. Now, this elegant paper shows that non-steroidal anti-inflammatory drugs (NSAIDs) prevent the emergence of cycling neurons in a transgenic (Tg) mouse model that mimics the alterations of the neuronal cell cycle found in the human AD brain.
This paper is informative in many ways. First, it hints at activated microglia cells as being essential players in the initiation of the neuronal cycle. Second, it indicates that microglia actvation is relevant to the generation of cycling neurons only in the presence of β amyloid. Third, it shows that NSAIDs prevent cell cycle initiation through the blockade of inflammation, but the drugs are not able to reverse the neuronal cycle once it is initiated. There is some good and bad in this demonstration. The bad is that NSAIDs...
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Evidence exists that cell death seen in AD arises from neurons attempting to divide, and this is why researchers working in the field believe that AD therapy might benefit from drugs able to arrest cell division in neurons. Until this paper by Varvel and colleagues, however, that hypothesis had not been truly tested. Now, this elegant paper shows that non-steroidal anti-inflammatory drugs (NSAIDs) prevent the emergence of cycling neurons in a transgenic (Tg) mouse model that mimics the alterations of the neuronal cell cycle found in the human AD brain.
This paper is informative in many ways. First, it hints at activated microglia cells as being essential players in the initiation of the neuronal cycle. Second, it indicates that microglia actvation is relevant to the generation of cycling neurons only in the presence of β amyloid. Third, it shows that NSAIDs prevent cell cycle initiation through the blockade of inflammation, but the drugs are not able to reverse the neuronal cycle once it is initiated. There is some good and bad in this demonstration. The bad is that NSAIDs do not seem valuable in treating subjects diagnosed with AD. The drugs might be potentially useful in preventing/delaying the onset of the disease, but we do not have definitive answers: 1) the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) had to be stopped ahead of time because of increased risk of cardiovascular and cerebrovascular events (PLoS Clin Trials, 2006); 2) evidence that NSAIDs reduce behavioral impairments in AD Tg mice is very thin (Lim et al., 2001) and, in same cases, it is unrelated to the anti-inflammatory properties of the drugs (Kukar et al., 2007). On the good side of the equation, we have a possible explanation for the disappointing results of clinical trials with NSAIDs in subjects with AD (Aisen et al., 2003). More important, from a research perspective, we might have a tool to monitor the effect of emerging drugs on the initiation and progression of AD-like neuropathology.
Karl Herrup’s lab has provided very convincing evidence that cell cycle events represent a biomarker for the risk of neurodegeneration in AD (Yang et al., 2003). However, because AD Tg mice do not develop frank neuronal loss, at the end we will need to assess how the neuronal cycle is related to the behavioral phenotype of Tg mice. The neuronal cycle is unique in the sense that it may last years. Currently, we are not able to predict to which extent we have to halt the cycle (do neurons need to re-enter quiescence or is it enough to block DNA replication?) to maintain/restore neuronal function. I believe that the upcoming goal is to see whether we can improve the cognitive impairment of AD Tg mice by using drugs that halt the neuronal cycle. The paper by Varvel and colleagues is a significant step toward this goal.
 View all comments by Agata Copani |
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Comment by: Jeroen Hoozemans
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Submitted 26 November 2009
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Posted 2 December 2009
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 I recommend the Primary Papers
Cell cycle changes can be detected in neurons that are vulnerable for developing neurodegenerative changes that are associated with Alzheimer disease (AD) pathology. The paper by Varvel and colleagues is very interesting, showing the potential of non-steroidal anti-inflammatory drugs (NSAIDs) to prevent neuronal cell cycle changes which can be found in the human AD brain.
Most NSAIDs inhibit the activity of cyclooxygenase (COX). Both isoforms, COX-1 and COX-2, are expressed in the brain with differences in cellular localization. Expression studies of COX-1 and COX-2 in AD brain have shown changes compared to non-demented control brains, suggesting a role for COX-1 and COX-2 in AD pathology. In their paper, Varvel and colleagues primarily focus on the effect of NSAID treatment on microglia activation, while no attention is paid to neuronal COX-2, whose expression is increased in the early stages of AD pathology (Ho et al., 2001; Hoozemans et al., 2001; Yermakova and O'Banion, 2001).
The expression of COX-2 in numerous types of cancer and the effect of selective COX-2...
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Cell cycle changes can be detected in neurons that are vulnerable for developing neurodegenerative changes that are associated with Alzheimer disease (AD) pathology. The paper by Varvel and colleagues is very interesting, showing the potential of non-steroidal anti-inflammatory drugs (NSAIDs) to prevent neuronal cell cycle changes which can be found in the human AD brain.
Most NSAIDs inhibit the activity of cyclooxygenase (COX). Both isoforms, COX-1 and COX-2, are expressed in the brain with differences in cellular localization. Expression studies of COX-1 and COX-2 in AD brain have shown changes compared to non-demented control brains, suggesting a role for COX-1 and COX-2 in AD pathology. In their paper, Varvel and colleagues primarily focus on the effect of NSAID treatment on microglia activation, while no attention is paid to neuronal COX-2, whose expression is increased in the early stages of AD pathology (Ho et al., 2001; Hoozemans et al., 2001; Yermakova and O'Banion, 2001).
The expression of COX-2 in numerous types of cancer and the effect of selective COX-2 inhibitors on tumor growth suggest a role for COX-2 in cell cycle regulation. Interestingly, COX-2 co-localizes with cell cycle proteins in AD neurons (Hoozemans et al., 2002; Mirjany et al., 2002; Hoozemans et al., 2004). Functional studies show that increased neuronal COX-2 expression leads to increased expression of cell cycle mediators in post-mitotic neurons, as shown in a transgenic mouse model with increased neuronal COX-2 expression (Xiang et al., 2002). In addition, COX-2 is required for cyclin D1 expression in neurons after ischemia in vivo and anoxia in vitro (Wu Chen et al., 2004). So while COX-2 and cell cycle proteins co-localize in AD neurons, COX-2 is also actively involved in the regulation of cell cycle control in these cells.
In their study, Varvel and colleagues nicely show that NSAID treatment prevents neuronal cell cycle protein expression by reducing microglia activation. Although it does not exclude that microglia or inflammation are involved in inducing increased expression of cell cycle proteins in neurons, clinico-pathological data indicate that neuronal cell cycle protein expression precedes the widespread activation of microglia in AD brain (Hoozemans et al., 2005). Alternatively, in the human brain, NSAIDs could directly affect cell cycle protein expression in neurons by selective inhibition of neuronal COX-2. Either way, there is increasing evidence that regular use of NSAIDs can lower risk of developing AD by preventing aberrant cell cycle protein expression in neurons.
References:
Ho, L., Purohit, D., Haroutunian, V., Luterman, J. D., Willis, F., Naslund, J., Buxbaum, J. D., Mohs, R. C., Aisen, P. S., and Pasinetti, G. M., 2001. Neuronal cyclooxygenase 2 expression in the hippocampal formation as a function of the clinical progression of Alzheimer disease. Arch Neurol 58, 487-92. Abstract
Hoozemans, J. J., Bruckner, M. K., Rozemuller, A. J., Veerhuis, R., Eikelenboom, P., and Arendt, T., 2002. Cyclin D1 and cyclin E are co-localized with cyclo-oxygenase 2 (COX-2) in pyramidal neurons in Alzheimer disease temporal cortex. J.Neuropathol.Exp.Neurol. 61, 678-688. Abstract
Hoozemans, J. J., Rozemuller, A. J., Janssen, I., de Groot, C. J., Veerhuis, R., and Eikelenboom, P., 2001. Cyclooxygenase expression in microglia and neurons in Alzheimer's disease and control brain. Acta Neuropathol (Berl) 101, 2-8. Abstract
Hoozemans, J. J., Van Haastert, E. S., Veerhuis, R., Arendt, T., Scheper, W., Eikelenboom, P., and Rozemuller, A. J., 2005. Maximal COX-2 and ppRb expression in neurons occurs during early Braak stages prior to the maximal activation of astrocytes and microglia in Alzheimer's disease. J Neuroinflammation 2, 27. Abstract
Hoozemans, J. J., Veerhuis, R., Rozemuller, A. J., Arendt, T., and Eikelenboom, P., 2004. Neuronal COX-2 expression and phosphorylation of pRb precede p38 MAPK activation and neurofibrillary changes in AD temporal cortex. Neurobiol.Dis. 15, 492-499. Abstract
Mirjany, M., Ho, L., and Pasinetti, G. M., 2002. Role of cyclooxygenase-2 in neuronal cell cycle activity and glutamate-mediated excitotoxicity. J Pharmacol Exp Ther 301, 494-500. Abstract
Wu Chen, R., Zhang, Y., Rose, M. E., and Graham, S. H., 2004. Cyclooxygenase-2 activity contributes to neuronal expression of cyclin D1 after anoxia/ischemia in vitro and in vivo. Brain Res Mol Brain Res 132, 31-7. Abstract
Xiang, Z., Ho, L., Valdellon, J., Borchelt, D., Kelley, K., Spielman, L., Aisen, P. S., and Pasinetti, G. M., 2002. Cyclooxygenase (COX)-2 and cell cycle activity in a transgenic mouse model of Alzheimer's disease neuropathology. Neurobiol Aging 23, 327-34. Abstract
Yermakova, A. V. and O'Banion, M. K., 2001. Downregulation of neuronal cyclooxygenase-2 expression in end stage Alzheimer's disease. Neurobiol Aging 22, 823-36. Abstract
View all comments by Jeroen Hoozemans |
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Comment by: Nicholas H. Varvel
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Submitted 2 December 2009
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Posted 2 December 2009
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I would like to take the opportunity to clarify a few points in the review pertaining to our work published in 2008. Over the past few years our goal has been to determine the insult(s) responsible for the induction of neuronal cell cycle events (CCEs) in mouse models of AD. Specifically, we explored the involvement of Aβ in the induction of CCEs. To accomplish this we analyzed CCEs in two different mouse models of AD and compared our findings to those obtained from R1.40 mice maintained on the C57BL/6J genetic background (B6-R1.40). First, R1.40 animals maintained on the DBA/2J (D2-R1.40) genetic background first exhibit neuronal CCEs at 12 months of age, six months after CCEs are first encountered in B6-R1.40 animals. While both B6-R1.40 and D2-R1.40 mice exhibit similar levels of both holo-APP and APP CTFs, the steady-state levels of Aβ are substantially reduced in the D2-R1.40 animals. These data indicate that reductions in Aβ levels delay the induction of CCEs. Second, B6-R1.40 mice deficient for Bace1 (B6-R1.40;Bace1-/-) exhibit no evidence of CTFβ and fail to develop...
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I would like to take the opportunity to clarify a few points in the review pertaining to our work published in 2008. Over the past few years our goal has been to determine the insult(s) responsible for the induction of neuronal cell cycle events (CCEs) in mouse models of AD. Specifically, we explored the involvement of Aβ in the induction of CCEs. To accomplish this we analyzed CCEs in two different mouse models of AD and compared our findings to those obtained from R1.40 mice maintained on the C57BL/6J genetic background (B6-R1.40). First, R1.40 animals maintained on the DBA/2J (D2-R1.40) genetic background first exhibit neuronal CCEs at 12 months of age, six months after CCEs are first encountered in B6-R1.40 animals. While both B6-R1.40 and D2-R1.40 mice exhibit similar levels of both holo-APP and APP CTFs, the steady-state levels of Aβ are substantially reduced in the D2-R1.40 animals. These data indicate that reductions in Aβ levels delay the induction of CCEs. Second, B6-R1.40 mice deficient for Bace1 (B6-R1.40;Bace1-/-) exhibit no evidence of CTFβ and fail to develop neuronal CCEs. These data indicate that CCEs are dependent on β-secretase activity and not γ-secretase activity as stated in the posted article. Genetic removal of Bace1 results in the inability to produce Aβ as well as CTFβ. Therefore, we cannot rule out CTFβ as the Bace1-dependent APP processing product that induces CCEs. However, D2-R1.40 exhibit similar steady-states levels of CTFβ when compared to B6-R1.40 animals. Thus, we concluded that Aβ must be involved in the induction of neuronal CCEs.
References: Varvel et. al. (2008) Abeta oligomers induce neuronal cell cycle events in Alzheimer's disease. Journal of Neuroscience. 28(43):10786-10793. Abstract
View all comments by Nicholas H. Varvel |
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