This report from Tommaso Russo’s group represents a small but growing number of studies that are focused not on Aβ-ology but on the function of APP. Continuing from their previous observation that Fe65 protects cells from DNA damage, this study provides strong evidence that APP is required for the Fe65 mediated DNA repair. Knockdown of APP/APLP2 resulted in impaired recruitment of Fe65-Tip60-TRRAP complex to the DNA break sites in the nucleus and reduced the repair efficiency. The authors mention that this unexpected role of APP should be taken into account as a possible mechanism contributing to neuronal dysfunction in AD.

These are important observations and would further stimulate experiments along the lines of APP function. One important issue that this study unfortunately did not address is whether or not the presence of AICD in the nucleus is essential for the observed effects of Fe65. Now that we have several excellent γ-secretase inhibitors available, this one should be an easy experiment to do. Although the Cao-Sudhof model suggests that the cleavage of APP is not...  Read more

This report from Tommaso Russo’s group represents a small but growing number of studies that are focused not on Aβ-ology but on the function of APP. Continuing from their previous observation that Fe65 protects cells from DNA damage, this study provides strong evidence that APP is required for the Fe65 mediated DNA repair. Knockdown of APP/APLP2 resulted in impaired recruitment of Fe65-Tip60-TRRAP complex to the DNA break sites in the nucleus and reduced the repair efficiency. The authors mention that this unexpected role of APP should be taken into account as a possible mechanism contributing to neuronal dysfunction in AD.

These are important observations and would further stimulate experiments along the lines of APP function. One important issue that this study unfortunately did not address is whether or not the presence of AICD in the nucleus is essential for the observed effects of Fe65. Now that we have several excellent γ-secretase inhibitors available, this one should be an easy experiment to do. Although the Cao-Sudhof model suggests that the cleavage of APP is not required and that mere association with APP-CTF at the cell surface is enough to “activate” Fe65 (open conformation), there is really no solid data to support such a notion. This scenario might be plausible in non-neuronal cells where the distance from cell surface to the nucleus is not insurmountable but less so in neuronal cells, where both APP and Fe65 are known to accumulate in the synapses or growth cones. In any case, these are interesting findings on the novel aspect of APP function, and one can be sure the Russo lab is examining the effects of γ-secretase inhibitors and APPswe or D664A mutation in their assay.

View all comments by Sanjay W. Pimplikar