Mutations in the presenilin 1 gene (PS1) are responsible for most cases of early onset familial Alzheimer's disease (FAD). These mutations are accompanied by an increase in β-amyloid peptides, in particular Aβ42. In cell culture, PS1 deletion results in a reduction of Aβ peptides, suggesting that inhibiting PS1 may be one possible therapeutic approach to controlling this disease. Such deletions have not been examined in vivo, however, as PS1 knockouts die in utero. In the September 13 Neuron, Jie Shen from the Center for Neurologic Diseases at Brigham and Women's Hospital, Massachusetts, and colleagues, have successfully raised PS1 conditional knockout mice to adulthood.
Morphologically, the hippocampus and neocortex of the cKO mice appeared normal. The mice exhibited a marked reduction in cortical PS1 expression beginning at age six weeks. Levels of amyloid precursor protein (APP) remained normal, even in six-month-old mice; however, levels of C-terminal fragments of APP had accumulated to 30-fold higher than normal by that age. In contrast, levels of the peptides Aβ40 and Aβ42, which are products of γ-secretase, were significantly reduced in three- to six-month-old animals, confirming previous in-vitro work as well as the suggestion that PS1 and γ-secretase are closely associated.
The mice appeared generally healthy. For example, though PS1 is required for embryonic Notch signaling, Notch's downstream targets were expressed normally. Likewise, synaptic transmission and plasticity were unaffected, though the animals did show a slight loss of long-term memory. The main value of the paper is showing that PS1-dependent γ-cleavage is active in adults, but it is hard to make firm conclusions about the effect on Notch signaling as only a limited number of Notch targets were examined, comments Edward Koo from the University of California San Diego.