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).
Increased neurogenesis in the dentate gyrus (Wines-Samuelson et al., 2010).
Available through Jie Shen.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
Tangles are absent, but hyperphosphorylation of tau has been reported in 9 month-old mice.
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).
Reduction in synaptophysin immunoreactivity in hippocampal CA1 pyramidal neurons by 6 months. Reduction in dendritic spines by 9 months (Saura et al., 2004).
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).