I am submitting this invited comment with the caveat that I have not had an opportunity to read the full text of this article. With that caveat in mind, it seems to me that this study is the in vivo correlate of the work published by McPhie and colleagues (see ARF related news story) using forced expression of similar APP sequences in primary neurons. In McPhie's study, cell cycle activation with DNA synthesis preceded apoptotic death of neurons. Assuming the expression of cell cycle proteins in APP23 mice (Gartner et al.) was examined at different time points, including aged mice, I wonder whether primary neurons are a reliable model for studies of cell cycle dysregulation in mature brain. I raised this point during the live cell cycle chat (ARF live discussion), emphasizing the immature nature of primary neuronal cultures—which is exactly the property that allows them to grow in vitro. Yet, McPhie's results are very intriguing—and taken together...  Read more

I am submitting this invited comment with the caveat that I have not had an opportunity to read the full text of this article. With that caveat in mind, it seems to me that this study is the in vivo correlate of the work published by McPhie and colleagues (see ARF related news story) using forced expression of similar APP sequences in primary neurons. In McPhie's study, cell cycle activation with DNA synthesis preceded apoptotic death of neurons. Assuming the expression of cell cycle proteins in APP23 mice (Gartner et al.) was examined at different time points, including aged mice, I wonder whether primary neurons are a reliable model for studies of cell cycle dysregulation in mature brain. I raised this point during the live cell cycle chat (ARF live discussion), emphasizing the immature nature of primary neuronal cultures—which is exactly the property that allows them to grow in vitro. Yet, McPhie's results are very intriguing—and taken together with Gartner's findings, suggest that APP mutations might not by themselves cause cell cycle dysregulation in mature terminally differentiated neurons, but may exacerbate this pathologic process once it has been triggered by other causes. Thus, some as yet unknown insult causes mature neurons to revert to a state resembling primary neurons, i.e., postmitotic but not completely differentiated, and the presence of pathologic APP mutations accelerates the cell cycle dysregulation. It may be possible to determine whether normal physiological APP is essential for the progressive cell cycle alterations in neurons by examining the effects of disrupting the APP gene in a model that already displays cell cycle alterations in vivo. The only such models I am aware of are the Harlequin and Niemann-Pick type C mice. Strangely, primary neurons from NPC-1 mice appear and survive normally in culture, while neurons in the brains of NPC-1 mice die in large numbers from seven weeks of age onward! I am so glad to see all these new papers on the cell cycle!!

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