Genes: APP, PSEN1
Mutations: PSEN1 R278I
Modification: APP: Transgenic; PSEN1: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6.Cg-Tg(Thy1-APP)3Somm/J; Psen1tm1.1Tcs
Genetic Background: C57BL/6J
Availability: Available through Takaomi Saido
This mouse model is a cross between a well-characterized APP transgenic (APP23) and a PSEN1 knock-in mouse (PS1-R278I) that expresses human PSEN1 with a mutation linked to atypical AD. The R278I mutation alters γ-secretase processing of APP, leading to unusually high levels Aβ43 with correspondingly low levels of Aβ40 due to impaired trimming of the Aβ43 peptide (Nakaya et al., 2005). Consistent with these in vitro findings, PS1-R278I mice and APP23 X PS1-R278I mice exhibit high levels of Aβ43 from an early age. The presence of the PSEN1 mutation in the double mutant accelerates plaque development and memory deficits relative to APP23 mice, suggesting that the skewed ratio of Aβ peptides, and perhaps elevated Aβ43 in particular, is deleterious (Saito et al., 2011).
Heterozygous PS1-R278I mice were used for the cross because homozygous mice die in utero due to insufficient γ-secretase activity. Heterozygous animals, on the other hand, develop normally despite a 50 percent reduction in γ-secretase activity. As expected, the heterozygous mice exhibit elevated levels of Aβ43 in brain fractions, and correspondingly low Aβ40. Although the heterozygous knock-in mice appear phenotypically normal as adults, it is unknown if additional behavioral and pathological analyses would reveal subtle abnormalities.
When crossed with APP23 mice, which overexpress APP with the Swedish mutation, the resulting progeny had accelerated plaque development and memory deficits relative to APP23 littermates. The double mutant started to accumulate Aβ deposits at 6 months of age, whereas the APP23 mice in this study did not develop a commensurate plaque load until 12 months of age. The double mutant also had a higher density of thioflavin-S positive plaques, suggesting that Aβ43 may foster core formation. Around 9 months of age, large numbers of reactive astrocytes were observed around plaques and pyroglutamate Aβ (N3pE-Aβ) co-localized with plaques.
Prior to plaque formation, a short-term memory deficit was observed in APP23 X PS1–R278I mice. At 3 to 4 months of age, the double mutant performed less well than APP23 mice in the Y maze. A similar deficit was seen in the Morris water maze, but it was not statistically significant.
Biochemical analysis showed that the brains of the double-mutant mice exhibited an early and selective increase in Aβ43 in the fraction extracted with Tris-HCl buffered saline as well as the fraction soluble in guanidine hydrochloride. Elevated Aβ43 was detectable at 3 months of age, which is prior to plaque deposition and coincident with memory impairment. Aβ40 and Aβ42 levels increased later, around 9 months of age.
This is a cross between APP23 mice, which overexpress APP751 with the Swedish mutation driven by the murine Thy1 promoter, and PSEN1 knock-in mice expressing human PSEN1 with the R278I mutation under the endogenous presenilin-1 promoter.
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
- Synaptic Loss
- Changes in LTP/LTD
By 6 months of age amyloid plaques accumulate in the cortex and hippocampus. A high percentage of plaques are thioflavin-S –positive cored plaques.
Astrocytosis in the vicinity of plaques in the hippocampus and cortex by 9 months.
Changes in LTP/LTD
Short-term memory deficits are apparent by 3 to 4 months as measured by the Y maze.
Research Models Citations
- Nakaya Y, Yamane T, Shiraishi H, Wang HQ, Matsubara E, Sato T, Dolios G, Wang R, De Strooper B, Shoji M, Komano H, Yanagisawa K, Ihara Y, Fraser P, St George-Hyslop P, Nishimura M. Random mutagenesis of presenilin-1 identifies novel mutants exclusively generating long amyloid beta-peptides. J Biol Chem. 2005 May 13;280(19):19070-7. PubMed.
- Saito T, Suemoto T, Brouwers N, Sleegers K, Funamoto S, Mihira N, Matsuba Y, Yamada K, Nilsson P, Takano J, Nishimura M, Iwata N, Van Broeckhoven C, Ihara Y, Saido TC. Potent amyloidogenicity and pathogenicity of Aβ43. Nat Neurosci. 2011 Aug;14(8):1023-32. PubMed.