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Gräff J, Rei D, Guan JS, Wang WY, Seo J, Hennig KM, Nieland TJ, Fass DM, Kao PF, Kahn M, Su SC, Samiei A, Joseph N, Haggarty SJ, Delalle I, Tsai LH. An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature. 2012 Mar 8;483(7388):222-6. PubMed.
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University of Wisconsin, Madison
Overall, this is a nice paper that is comprehensive in its approach. The use of two different Alzheimer’s disease (AD) mouse models is a strength of the paper. Of course, none of these AD models fully reflects the human AD pathology, and it is always uncertain how these findings will translate to the human system. The gene expression studies demonstrating HDAC2-dependent repression of synaptic target genes in the AD mouse models was compelling. The gene expression changes will require additional study, as only a handful of genes were tested. Which of these genes is most critical to reversing the pathology is of interest, but will be hard to address. The fact that HDAC2 binds to many of the downregulated genes supports a causal role for HDAC2-mediated repression in the associated learning and memory defects. However, this is not an easy thing to prove; it is possible that HDAC2 knockdown reverses a different pathologic process, and that the gene expression changes are a secondary consequence. Of course, this does not diminish the fact that HDAC2 appears to be an interesting target. Although selective targeting of HDAC2 is certainly indicated from this study, it may be difficult given its high degree of similarity to HDAC1. In sum, the idea that crucial neuronal genes are epigenetically and reversibly downregulated in experimental AD is supported by the data. This would imply, as the authors suggest, that some of the deficits in human AD may be reversible, which should create excitement in the community, especially given the fact that HDAC inhibitors are currently being explored in the clinic for a variety of conditions.
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