Transgene: To generate forebrain-specific PS conditional double knockout (PS
cDKO) mice, we crossed
floxed PS1 (fPS1), αCaMKII-Cre transgenic mice and
mice together to obtain fPS1/fPS1;αCaMKII-Cre;PS2-/- mice.
Genetic Background: fPS1/fPS1 and PS2-/- mice were
generated in C57BL6/129 hybrid background, whereas αCaM-Cre
transgenic mice were generated in C57BL6/CBA hybrid strain and then backcrossed
to B6 for more than 10 generations. Therefore, the genetic background of all experimental
groups was C57BL6/129 hybrid.
cDKO mice lacking both presenilins in the postnatal forebrain exhibit impairments
in hippocampal memory and synaptic plasticity. These deficits are associated with
specific reductions in NMDA receptor-mediated responses and synaptic levels of NMDA
receptors and αCaMKII.
Furthermore, loss of presenilins causes reduced expression of CBP and CREB/CBP target
genes, such as c-fos and BDNF. With increasing age, mutant mice develop striking
neurodegeneration of the cerebral cortex and worsening impairments of memory and
synaptic function. Increased levels of the Cdk5 activator p25 and hyperphosphorylated
tau accompany neurodegeneration.
During early adulthood, PS
cDKO mice are viable and indistinguishable from littermate controls. Open field
and rotarod tests of PS cDKO mice at 2-3 months of age revealed no significant alterations
in general behavior, motor coordination, and exploratory anxiety.
Center for Neurologic Diseases
Brigham and Women's Hospital, Program in Neuroscience
Harvard Medical School
Boston, MA 02115, USA
Saura CA, Choi SY, Beglopoulos V, Malkani S, Zhang D, Shankaranarayana Rao BS, Chattarji
S, Kelleher RJ, Kandel ER, Duff K, Kirkwood A, Shen J. Loss of presenilin function
causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration.
Neuron. 2004 Apr 8 ; 42(1):23-36.