This study is arguably the most comprehensive study of FAD-linked PS mutations with respect to effects on secreted and intracellular Abeta production. Although there are only a few aspects of the study that are truly novel, some of the more subtle aspects of effects of PS mutants on Abeta are rigorously documented. For example, it is clearly shown in this paper that many FAD-linked PS mutants reduce Abeta40 production and increase Abeta42 production, through direct alterations in gamma-secretase activity. Other mutations only increase Abeta42 production with little effect on Abeta40. Thus, there are subtle but important distinctions between the alterations induced by various PS mutations. In this regard one might classify some PS mutants as "shift in function" and others as mixed "loss of function with a corresponding shift in function." The only concern with these studies is that they are carried out in a heterologous cell background (CHO cells). It will be interesting to see if similar findings are seen when the same mutants are expressed in a PS null background or in human...  Read more

This study is arguably the most comprehensive study of FAD-linked PS mutations with respect to effects on secreted and intracellular Abeta production. Although there are only a few aspects of the study that are truly novel, some of the more subtle aspects of effects of PS mutants on Abeta are rigorously documented. For example, it is clearly shown in this paper that many FAD-linked PS mutants reduce Abeta40 production and increase Abeta42 production, through direct alterations in gamma-secretase activity. Other mutations only increase Abeta42 production with little effect on Abeta40. Thus, there are subtle but important distinctions between the alterations induced by various PS mutations. In this regard one might classify some PS mutants as "shift in function" and others as mixed "loss of function with a corresponding shift in function." The only concern with these studies is that they are carried out in a heterologous cell background (CHO cells). It will be interesting to see if similar findings are seen when the same mutants are expressed in a PS null background or in human cells.

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