Research Models

PS cDKO

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

Summary

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).

Neuropathology

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).

Cognition/Behavior

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).

Availability

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+.

Absent

  • Plaques
  • Tangles

No Data

Plaques

Absent.

Tangles

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.

Gliosis

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). 

COMMENTS / QUESTIONS

  1. We are very intrigued by the two recent papers (Feng et al., 2004; Saura et al., 2004) showing neurodegeneration and tau hyperphosphorylation in PS null mouse brains. Although at first sight the non-amyloid neuropathology doesn’t appear to be directly relevant to AD, these studies nevertheless clearly challenge the currently widely accepted view that AD-related PS mutations are gain of function mutations (as measured by amyloid-β deposition/secretion).

    In this context, it is of interest that we have recently published a paper (Dermaut et al., 2004) reporting a novel PS1 mutation in a patient with a pure tauopathy (Pick’s disease, a subtype of FTD) but without any detectable amyloid deposits. Moreover, preliminary evidence on the molecular nature of this mutation suggests that it might act as a partial loss-of-function allele due to aberrant exon splicing, which would be in agreement with the loss of function/dominant negative mechanism that has been proposed for another PS1 mutation (insArg352) associated with FTD, though not pathologically confirmed (Amtul et al., 2002; Tang-Wai et al., 2002). In addition, we have shown that lowered neuronal expression of PS is genetic risk factor for early onset AD (Theuns et al., 2003), Although still highly speculative, these studies together appear to raise the exciting possibility that, in humans, partial loss of PS function could result in primarily tau-mediated neurodegenerative pathways.

    References:

    . A presenilin 1 mutation associated with familial frontotemporal dementia inhibits gamma-secretase cleavage of APP and notch. Neurobiol Dis. 2002 Mar;9(2):269-73. PubMed.

    . A novel presenilin 1 mutation associated with Pick's disease but not beta-amyloid plaques. Ann Neurol. 2004 May;55(5):617-26. PubMed.

    . Forebrain degeneration and ventricle enlargement caused by double knockout of Alzheimer's presenilin-1 and presenilin-2. Proc Natl Acad Sci U S A. 2004 May 25;101(21):8162-7. PubMed.

    . 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.

    . Familial frontotemporal dementia associated with a novel presenilin-1 mutation. Dement Geriatr Cogn Disord. 2002;14(1):13-21. PubMed.

    . Alzheimer-associated C allele of the promoter polymorphism -22C>T causes a critical neuron-specific decrease of presenilin 1 expression. Hum Mol Genet. 2003 Apr 15;12(8):869-77. PubMed.

    View all comments by Bart Dermaut

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References

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