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
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).
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.
Reduction in Aβ40 and Aβ42 peptides; accumulation of APP C-terminal fragments (Yu et al., 2001).
Subtle but significant deficits in long-term spatial memory in the Morris water maze (Yu et al., 2001).
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Neuronal Loss
- Changes in LTP/LTD
- Synaptic Loss
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).
Mild impairment of spatial learning and memory in the Morris water maze observed in 5 month-old mice (Yu et al., 2001).