Research Models


Synonyms: PS1 + APP, PSAPP, APP/PS1, APP/PS1 double transgenic

Species: Mouse
Genes: APP, PSEN1
Mutations: APP KM670/671NL (Swedish), PSEN1 M146L (A>C)
Modification: APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: B6/D2/Swe/SJL mixed background
Availability: Tg2576: Taconic (Stock #001349) and Charles River; PS1(M146L): University of South Florida Technology Transfer Office; double transgenic: also available at the CRO PsychoGenics


This double transgenic mouse was generated by crossing the well-established APP mutant line, Tg2576, with a line expressing mutant PSEN1, PS1(M146L). Double transgenics begin to accumulate Aβ42(43) at a young age and develop large numbers of fibrillar Aβ deposits in the cerebral cortex and hippocampus at about six months of age, considerably earlier than the single transgenic, Tg2576. Plaque pathology is not only accelerated, but enhanced in the double transgenic, with Aβ deposits eventually occupying a large area of the neocortex and hippocampus by 16 months. In parallel, there is a substantial increase in plaque-associated astrocytes and microglia, suggesting an overall increase in neuroinflammation between the ages of six and 16 months of age. Before overt Aβ deposition, the double transgenics show a selective increase in brain levels of Aβ42(43) compared to Tg2576 mice, which have stable peptide levels at this age (Holcomb et al., 1998).

The behavior of these animals has been extensively characterized and they have been shown to exhibit impairments in some, but not all, cognitive tests. They reportedly show normal water maze learning at six and nine months (Holcomb et al., 1999), but like single transgenic Tg2576 animals, they have impairments in Y-maze alternation at a young age (about three months) before substantial Aβ deposition, suggesting that this form of spatial memory may be independent of amyloid deposition (Holcomb et al., 1998; Holcomb et al., 1999). They exhibit progressive, age-related impairments in other cognitive tasks, including acquisition in the water maze and radial arm water maze working memory. Performance in these tasks deteriorates by 15-17 months compared with performance at 5–7 months when neuropathology is minimal (Arendash et al., 2001).


Large amounts of Aβ accumulate in the cerebral cortex and hippocampus, starting around 6 months and increasing with age. Other brain regions are affected later. Deposition occurs in white matter and the cerebrovasculature in addition to grey matter. Both diffuse and fibrillar plaques form. Fibrillar deposits are associated with dystrophic neurites and activated GFAP-positive, astrocytes early (about six months) with later microglial activation (about 12 months) (Gordon et al., 2002).

Modification Details

These double transgenic mice were generated by crossing Tg2576 mice, which overexpress human APP with the Swedish mutation driven by the hamster prion protein gene promoter, with mice overexpressing human PSEN1 with the M146L mutation driven by the PDGF-β promoter (PS1(M146L), line 5.1). The two transgenes segregate independently.


PS/APP mice have also been created that are the result of crosses between Tg2576 and PSEN1(M146V) mutant lines, the later first described in Duff et al., 1996. For example, see McGowan et al., 1999 for data pertaining to the Tg2576 x PS1(M146V) double transgenic.


The double transgenic is available at the CRO PsychoGenics. As single transgenics, Tg2576 are available through Taconic and Charles River and PsychoGenics. PS1(M146L) mice are available through the University of South Florida Technology Transfer Office and at PsychoGenics.

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+.


  • Tangles

No Data

  • Synaptic Loss
  • Changes in LTP/LTD


Large amounts of Aβ accumulate in the cerebral cortex and hippocampus, starting around 6 months and increasing with age. Other brain regions are affected later. Both diffuse and fibrillar plaques form (Gordon et al., 2002).


Neurofibrillary tangles are not associated with this model, but hyperphosphorylated tau is detected, starting at 24 weeks, appearing as punctate deposits near amyloid deposits in the cortex and hippocampus (Kurt et al., 2003).

Neuronal Loss

Neuronal loss in the CA1 region of the hippocampus has been reported at 22 months accompanied by reduced glucose utilization (Sadowski et al., 2004).


GFAP-positive astrocytes appear first in the cortex in the vicinity of the developing Aβ deposits. Numbers increase with age, becoming confluent. Numbers of resting microglia (positive for complement receptor-3) increase in the vicinity of deposits at 6 months, but activated microglia (positive for MHC-II) are negligible before 12 months and more variable (Gordon et al., 2002).

Synaptic Loss


Changes in LTP/LTD


Cognitive Impairment

Double and single transgenic mice had reduced spontaneous alternation performance in a “Y” maze, a test of spatial memory, at 12-14 weeks, before substantial Aβ deposition (Holcomb et al., 1998). Progressive age-related cognitive impairment is seen later in select tasks (e.g. water maze acquisition and radial arm water maze working memory)(Arendash et al., 2001).


  1. Undoubtedly this paper indicates an AD model to show neuropathological change and enables us to analyze the detailed study. It is important to be aware that the behavioral change appears before neuropathological changes such as the plaque formation.

    View all comments by Hiroshi Mori

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Research Models Citations

  1. PS1(M146L)
  2. PS1(M146V)

Paper Citations

  1. . Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med. 1998 Jan;4(1):97-100. PubMed.
  2. . Behavioral changes in transgenic mice expressing both amyloid precursor protein and presenilin-1 mutations: lack of association with amyloid deposits. Behav Genet. 1999 May;29(3):177-85. PubMed.
  3. . Progressive, age-related behavioral impairments in transgenic mice carrying both mutant amyloid precursor protein and presenilin-1 transgenes. Brain Res. 2001 Feb 9;891(1-2):42-53. PubMed.
  4. . Time course of the development of Alzheimer-like pathology in the doubly transgenic PS1+APP mouse. Exp Neurol. 2002 Feb;173(2):183-95. PubMed.
  5. . Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature. 1996 Oct 24;383(6602):710-3. PubMed.
  6. . Amyloid phenotype characterization of transgenic mice overexpressing both mutant amyloid precursor protein and mutant presenilin 1 transgenes. Neurobiol Dis. 1999 Aug;6(4):231-44. PubMed.

Other Citations

  1. Tg2576

External Citations

  1. PsychoGenics
  2. Taconic
  3. Charles River
  4. Taconic (Stock #001349)
  5. Charles River
  6. PsychoGenics

Further Reading


  1. . Neurodegenerative changes associated with beta-amyloid deposition in the brains of mice carrying mutant amyloid precursor protein and mutant presenilin-1 transgenes. Exp Neurol. 2001 Sep;171(1):59-71. PubMed.
  2. . Hyperphosphorylated tau and paired helical filament-like structures in the brains of mice carrying mutant amyloid precursor protein and mutant presenilin-1 transgenes. Neurobiol Dis. 2003 Oct;14(1):89-97. PubMed.
  3. . A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature. 2000 Dec 21-28;408(6815):982-5. PubMed.
  4. . Amyloid-beta deposition is associated with decreased hippocampal glucose metabolism and spatial memory impairment in APP/PS1 mice. J Neuropathol Exp Neurol. 2004 May;63(5):418-28. PubMed.