Research Models

PS1 cKO

Synonyms: PS1 conditional KO, PSEN1 conditional KO

Species: Mouse
Genes: PSEN1
Modification: PSEN1: Conditional Knock-out
Disease Relevance: Alzheimer's Disease
Strain Name: fPS1/fPS1;αCaMKII-Cre
Genetic Background: CaM-Cre tg mice were generated in C57BL/6J x CBA hybrid, and then back-crossed several generations to C57BL/6J. The floxed PS1 mouse was generated in C57BL/6J and 129/Sv hybrid.
Availability: Available through Jie Shen

Summary

PSEN1 conditional knockout (PS1 cKO) mice were generated from a Cre/lox recombination system. With this strategy PSEN1 expression is progressively eliminated from the neocortex and hippocampus beginning in the third postnatal week. Briefly, mice carrying a modified floxed PS1 allele (fPS1) were crossed with a Cre transgenic mouse (CaM-Cre), in which Cre recombinase is expressed selectively in pyramidal neurons of the postnatal forebrain under the control of the α-calcium-calmodulin-dependent kinase II (αCaMKII) promoter. The PS1 cKO mouse was then generated by crossing the fPS1 mouse to the CaM-Cre transgenic mouse. In contrast to PS1-/- mice, PS1 cKO mice are viable and exhibit no obvious phenotypic abnormalities (Yu et al., 2001).   

PS1 cKO mice have lower levels of both murine and human Aβ40 and Aβ42 in the adult cortex and elevated APP C-terminal fragments. Although basal synaptic transmission, long-term potentiation, and long-term depression at hippocampal CA1 synapses are normal, five month-old PS1 cKO mice exhibit subtle but significant deficits in long-term spatial memory as measured by the Morris water maze. 

When PS1 cKO mice were crossed with the J20 line of APP transgenic mice overexpressing human APP carrying both Swedish and Indiana mutations, the accumulation of Aβ peptides and amyloid plaques in the J20 mice was reduced, but APP C-terminal fragments accumulated to very high levels. PS1 inactivation failed to improve cognitive and physiological impairment associated with older APP transgenic mice (Saura et al., 2005).

Modification Details

PS1 conditional KO mice have a selective deletion of PSEN1 in excitatory neurons of the forebrain beginning at about one month of age. They were generated by crossing a floxed PS1 mouse with a CamKII-Cre transgenic mouse. 

Neuropathology

Reduction in Aβ40 and Aβ42 peptides; accumulation of APP C-terminal fragments (Yu et al., 2001).

Cognition/Behavior

Subtle but significant deficits in long-term spatial memory in the Morris water maze (Yu et al., 2001).

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

  • Neuronal Loss
  • Plaques
  • Tangles
  • Changes in LTP/LTD

No Data

  • Gliosis
  • Synaptic Loss

Plaques

Absent.

Tangles

Absent.

Neuronal Loss

Absent.

Gliosis

Unknown.

Synaptic Loss

Unknown.

Changes in LTP/LTD

Mice at 3-6 months of age exhibit normal paired-pulse facilitation, LTP, and LTD in the Schaffer collateral pathway of the hippocampus (Yu et al., 2001).

Cognitive Impairment

Mild impairment of spatial learning and memory in the Morris water maze observed in 5 month-old mice (Yu et al., 2001).

COMMENTS / QUESTIONS

  1. Keeping in mind everything that is currently known about PS1 and its main substrate, APP, this paper by Yu et al. was a pioneer in studying the consequences of PS1 inactivation on cognitive deficit. Despite not being recent, there are still some ideas that can be drawn from reading it.

    In the cortex of the PS1 cKO mouse, two carboxy-terminal fragments, C89 and C83, were clearly increased as a result of increased availability of substrate, APP, for the cleavage reactions of α- and β-secretase, respectively. Both were elevated by as much as 30-fold (Figure 4 of the paper), whereas C99, another β-secretase cleavage product, was only increased threefold.

    Apart from the increased availability of APP for β cleavage, less than half of the total amount of Aβ (Aβ40 and Aβ42) forms in the cortex of PS1 cKO mouse cortex compared to control (Table 2 of paper), because less than half of the amount of C99 is cleaved by γ-secretase. In other words, something has happened with γ cleavage, because PS1 was conditionally knocked out. But in addition, the relatively small increase in C99 is curious, since overexpression of BACE leads to robust increases in C99 over C89 (see Lee et al., 2005). Why the small increase in C99 in PS1 knockouts? It seems that in this case, BACE C99 cleavage is linked to PS1, suggesting that APP might have to be physically attached to the γ-secretase complex before C99 β cleavage occurs.

    References:

    . BACE overexpression alters the subcellular processing of APP and inhibits Abeta deposition in vivo. J Cell Biol. 2005 Jan 17;168(2):291-302. PubMed.

    View all comments by Miguel Rodríguez-Manotas

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References

Research Models Citations

  1. J20 (PDGF-APPSw,Ind)

Paper Citations

  1. . APP processing and synaptic plasticity in presenilin-1 conditional knockout mice. Neuron. 2001 Sep 13;31(5):713-26. PubMed.
  2. . Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic mice. J Neurosci. 2005 Jul 20;25(29):6755-64. PubMed.

Other Citations

  1. Jie Shen

Further Reading

No Available Further Reading