Genes: APP, PSEN1
Mutations: APP KM670/671NL, APP V717F (Indiana), PSEN1 L166P
Modification: APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: Fischer 344
APP+PS1 transgenic rats express human APP with the Swedish and Indiana mutations and human PSEN1 with the L166P mutation. Both transgenes are driven by the ubiquitin-C promoter. These rats exhibit amyloid pathology, neurodegeneration, and behavioral deficits.
To generate this line, a lentivral vector containing PSEN1 was injected into zygotes of homozygous APP21 rats (Agca et al., 2016). A founder animal with one copy of the PSEN1 transgene and relatively high levels of serum Aβ42, compared with other founders, was selected to establish this double-transgenic line. APP+PS1 rats are maintained as homozygous for the APP transgene and hemizygous for the PSEN1 transgene, as rats homozygous for both transgenes are infertile.
Levels of Aβ40 in serum were similar in APP21 and APP+PS1 rats, measured at 30–50 days (Agca et al., 2016) and 19 months (Klakotskaia et al., 2018) of age. However, levels of serum Aβ42 were greater in APP+PS1 rats, by approximately twofold at 50 days and almost sixfold at 19 months.
While extracellular amyloid deposits have not been observed in APP21 rats up to 30 months of age (Agca et al., 2016), amyloid plaques and cerebral amyloid angiopathy were seen in 19-month-old female APP+PS1 rats (data are not available from males) (Klakotskaia et al., 2018). Tau immunoreactivity was associated with densely-stained plaques, suggesting the presence of dystrophic neurites. Cerebral amyloid angiopathy was accompanied by perivascular edema and hemorrhage. The number of necrotic neurons in the hippocampi and cortices of APP+PS1 rats was more than double that seen in non-transgenic animals, while the number in APP21 rats was intermediate between the two other genotypes (Agca et al., 2016; Klakotskaia et al., 2018).
Deficits in the acquisition, retention, and reversal phases of a Barnes maze task were apparent by 10 months of age (Agca et al., 2016).
A lentivirus vector containing human PSEN1 cDNA (coding region corresponding to bases 285–1688 of PSEN1 variant 1 (GenBank Accession number NM_000021.3)) with the L166P mutation was injected into homozygous APP21 zygotes (Agca et al., 2016).
APP21. APP21 rats express human APP695 containing the Swedish and Indiana mutations, driven by the ubiquitin-C promoter (Agca et al., 2008). Although these rats do not spontaneously develop amyloid pathology, they can serve as hosts for exogenously seeded amyloid deposits (Rosen et al., 2012). Behavioral deficits in the Barnes maze were reported in female rats by 14 months of age (Klakotskaia et al., 2018).
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Synaptic Loss
- Changes in LTP/LTD
Abundant plaques in hippocampus and subiculum, scattered plaques in cortex.
Necrotic neurons in hippocampus and cortex.
Changes in LTP/LTD
Deficits in Barnes maze at 10 months.
Last Updated: 31 Aug 2018
Research Models Citations
- Agca C, Klakotskaia D, Schachtman TR, Chan AW, Lah JJ, Agca Y. Presenilin 1 transgene addition to amyloid precursor protein overexpressing transgenic rats increases amyloid beta 42 levels and results in loss of memory retention. BMC Neurosci. 2016 Jul 7;17(1):46. PubMed.
- Klakotskaia D, Agca C, Richardson RA, Stopa EG, Schachtman TR, Agca Y. Memory deficiency, cerebral amyloid angiopathy, and amyloid-β plaques in APP+PS1 double transgenic rat model of Alzheimer's disease. PLoS One. 2018;13(4):e0195469. Epub 2018 Apr 11 PubMed.
- Agca C, Fritz JJ, Walker LC, Levey AI, Chan AW, Lah JJ, Agca Y. Development of transgenic rats producing human beta-amyloid precursor protein as a model for Alzheimer's disease: transgene and endogenous APP genes are regulated tissue-specifically. BMC Neurosci. 2008;9:28. PubMed.
- Rosen RF, Fritz JJ, Dooyema J, Cintron AF, Hamaguchi T, Lah JJ, LeVine H 3rd, Jucker M, Walker LC. Exogenous seeding of cerebral β-amyloid deposition in βAPP-transgenic rats. J Neurochem. 2012 Mar;120(5):660-6. Epub 2011 Nov 18 PubMed.
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