24 September 2001. 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 g-secretase,
were significantly reduced in three- to six-month-old animals, confirming previous in-vitro
work as well as the suggestion that PS1 and g-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 g-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.-Tom Fagan.
Reference:Yu H, Saura CA, Choi SY, Sun LD, Yang X, Handler M, Kawarabayashi T, Younkin L, Fedeles B, Wilson MA, Younkin S, Kandel ER, Kirkwood A, Shen J. APP processing and synaptic plasticity in presenilin-1 conditional knockout mice. Neuron. 2001 Sep 13;31(5):713-26. Abstract