Research Models


Synonyms: PS1/PS2 cDKO, PSEN1/PSEN2 conditional double knock-out

Species: Mouse
Genes: PSEN1, PSEN2
Modification: PSEN1: Conditional Knock-out; PSEN2: Knock-Out
Disease Relevance: Alzheimer's Disease
Strain Name: fPS1/fPS1;αCaMKII-Cre;PS2-/-
Genetic Background: C57BL6/129 hybrid
Availability: Available through Jie Shen


To generate postnatal forebrain-specific conditional double knock-out mice lacking both PSEN1 and PSEN2 (PS cDKO) mice, floxed PS1 (fPS1), αCaMKII-Cre transgenic mice and PS2-/- mice were bred together. This cross results in mice that have PSEN1 conditional deletion in excitatory neurons of the postnatal forebrain beginning about one month of age along with a PSEN2 germline deletion (Saura et al., 2004). PS cDKO mice are viable and are indistinguishable from littermate controls during early adulthood. Levels of Aβ40 and Aβ42 in the cortex are reduced and APP C-terminal fragments accumulate (Beglopoulos et al., 2004).

Open field and rotarod tests revealed no significant alterations in behavior, motor coordination, or exploratory anxiety at two to three months of age. However, two month-old PS cDKO mice exhibit mild impairments in hippocampal learning and memory as indicated by the Morris water maze and contextual fear conditioning. By six months of age, PS cDKO mice failed to learn the water maze and contextual fear conditioning tasks and also exhibited deficits in open field and rotarod tests (Saura et al., 2004).

PS cDKO mice develop synaptic deficits in the Schaffer collateral pathway of the hippocampus in an age-dependent manner. For example, at five weeks of age, synaptic facilitation is impaired, followed by NMDA receptor-mediated functional deficits at six weeks of age. The lack of presenilins also results in impaired neurotransmitter release probability, calcium induced calcium release, ryanodine receptor mediated calcium release from the ER, and ryanodine receptor levels and function. However, LTD, use-dependent depression, and IP3R function are normal (Zhang et al., 2010, Zhang et al., 2009, Wu et al., 2013).


At two months of age, the number of apoptotic neurons is elevated about 8-fold. By six months, about 18 percent of of cortical neurons are lost. Up-regulation of inflammatory markers and progressive astrogliosis and microgliosis in the neocortex and hippocampus have also been reported (Beglopoulos et al., 2004; Wines-Samuelson et al., 2010).


Impairments in hippocampal learning and memory as indicated by Morris water maze and contextual fear conditioning evident by two months which worsens with age (Saura et al., 2004).

Other Phenotypes

Increased neurogenesis in the dentate gyrus (Wines-Samuelson et al., 2010).


Available through Jie Shen.

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.


  • Plaques
  • Tangles

No Data




Tangles are absent, but hyperphosphorylation of tau has been reported in 9 month-old mice.

Neuronal Loss

Significant increase (about 8-fold) in apoptotic neurons at 2 months of age, although the total number of cortical neurons is not significantly altered due to the low basal level of apoptosis in the cerebral cortex. By 4 months of age, the cumulative loss of cortical neurons reaches about 9 percent of all cortical neurons.


Astrogliosis and microgliosis; up-regulation of GFAP and other inflammatory markers are observed in the neocortex and hippocampus at 6 months, and this increases with age (Wines-Samuelson et al., 2010, Beglopoulos et al., 2004). 

Synaptic Loss

Reduction in synaptophysin immunoreactivity in hippocampal CA1 pyramidal neurons by 6 months. Reduction in dendritic spines by 9 months (Saura et al., 2004).

Cognitive Impairment

Deficits in the Morris water maze and contextual fear conditioning are mild at 2 months, but become more severe with age (Saura et al., 2004). 



No Available Comments

Make a comment or submit a question

To make a comment you must login or register.


Paper Citations

  1. . Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron. 2004 Apr 8;42(1):23-36. PubMed.
  2. . Reduced beta-amyloid production and increased inflammatory responses in presenilin conditional knock-out mice. J Biol Chem. 2004 Nov 5;279(45):46907-14. Epub 2004 Sep 1 PubMed.
  3. . Inactivation of presenilins causes pre-synaptic impairment prior to post-synaptic dysfunction. J Neurochem. 2010 Dec;115(5):1215-21. Epub 2010 Oct 26 PubMed.
  4. . Presenilins are essential for regulating neurotransmitter release. Nature. 2009 Jul 30;460(7255):632-6. PubMed.
  5. . Presenilins regulate calcium homeostasis and presynaptic function via ryanodine receptors in hippocampal neurons. Proc Natl Acad Sci U S A. 2013 Sep 10;110(37):15091-6. Epub 2013 Aug 5 PubMed.
  6. . Characterization of age-dependent and progressive cortical neuronal degeneration in presenilin conditional mutant mice. PLoS One. 2010 Apr 15;5(4):e10195. PubMed.

Other Citations

  1. Jie Shen

Further Reading

No Available Further Reading