It has been assumed by many in the Alzheimer's disease (AD) field that presenilin-1 (PS1) FAD mutations represent a gain-of-function, in which altered processing of Abeta caused by the FAD mutants leads to neurodegeneration. However, this paper and the recent Neuron paper from Jie Shen's laboratory present compelling evidence that PS1 FAD mutations are actually loss-of-function mutations. Shen and colleagues showed that conditional knockouts of PS1 in the forebrain lead to many AD-like symptoms, both anatomical and behavioral, that are also seen in FAD mutant transgenic mice. In the present paper, Elder and colleagues demonstrate that the survival of BrdU-labeled neuronal progenitor cells is impaired in adult mice transgenic for a PS1 FAD mutation. This phenotype is similar to that described for a forebrain-specific PS1 knockout mouse, again suggesting a loss of function. These papers indicate that knowledge of the normal function of the presenilins almost certainly will enhance our understanding of AD neurodegeneration, in which PS1 function goes awry.

View all comments by Rachael Neve