. NSAIDs prevent, but do not reverse, neuronal cell cycle reentry in a mouse model of Alzheimer disease. J Clin Invest. 2009 Dec;119(12):3692-702. PubMed.

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  1. 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.

    References:

    . Ibuprofen effects on Alzheimer pathology and open field activity in APPsw transgenic mice. Neurobiol Aging. 2001 Nov-Dec;22(6):983-91. PubMed.

    . Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice. BMC Neurosci. 2007;8:54. PubMed.

    . Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA. 2003 Jun 4;289(21):2819-26. PubMed.

    . 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. PubMed.

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  1. Curbing Cell Cycle Re-entry: Window of Opportunity for NSAIDs?