. DNA replication precedes neuronal cell death in Alzheimer's disease. J Neurosci. 2001 Apr 15;21(8):2661-8. PubMed.

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  1. The data from Karl Herrup's lab are extremely fascinating. One of the issues with cell cycle genes in AD is whether the expression of these genes is coordinated as in an orderly progression of the cell cycle or whether these genes are subverted to other uses. And, if they are expressions of a "true" cell cycle, how far does the cycle get in these non-dividing cells? I think that Karl's work provides important insights into these issues. It is interesting to me that these extra chromosomes have not been reported previously. In fact, when people first became excited about a relationship between Down's and AD there were studies on extra chromosome 21 in AD that were negative. Incidentally, several years ago I collaborated on an epidemeological study of AD and cancer, with exactly the thought that Karl expressed. We used the extensive clinical data base at the Marshfield Clinic (Wisconsin) to look for an association between cancer and AD. At first pass the data suggested if you have one there is an increased probability of having the other. However, since both these are age-related morbidities. When the effect of age was factored out, the association disappeared.

  2. This paper from Karl Herrup and colleagues is really fantastic. I saw some of the data in Washington, and realized that this was an extremely well done and important experiment. It appeares to show that neurons in the AD brain have at least attempted to enter S phase, and probably are stuck in some kind of abortive attampt at cell division. I think it is very strong evidence that these neurons have received some kind of mitotic signal: I know some people will say "amyloid' right away. And there are people like Carol Troy, Lloyd Greene and others who have suggested that apoptosis in neurons in AD proceeds by a mechanism that may involve activation of the cell cycle, or at least elements of the cell cycle. Herrup's data is clearest yet to show that this mechanism involves at least some duplication of DNA, which could only result from an attempt at mitotis. So what happens if a differentiated neuron tries to divide? Alzheimer's disease, apparently!

  3. This paper emphasizes the apparent DNA replication of all chromosomes in neurons in AD patients, rather than also mentioning the aneuploidy for specific chromosomes including chromosome 21 that he reported last summer and which is equally consistent with the data shown. Unfortunately, the authors do not break down their data into trisomy vs tetrasomy/tetraploid cells and do not present any separate data obtained with the different chromosome probes. Thus it is not possible to tell from the paper how much aneuploidy vs reduplication of all DNA that they see. Indeed, since they do not use double labelling, each cell that is aneuploid for one chromosome could be either aneuploid or normal for another. There is no way to know. They choose to interpret the data as showing that many cells have completley duplicated their chromosomes, but the data could be equally interpretted as indicating that many cells have undergone chromosome mis-segrgeation in a random way that leaves them with incorrect chromosome complement.