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APP/PS1 double transgenic mice

Jiangsu Aniphe BioLab possesses a stable resource of APP/PS1 double-transgenic mice. Leveraging a standardized breeding and genotyping system, it can provide models at various ages and disease stages. With stable phenotypes and consistent batch-to-batch performance, these models can rapidly support Alzheimer’s disease mechanism research and drug efficacy evaluation, helping to shorten the R&D cycle.

Strain Introduction

The APP/PS1 double-transgenic mouse, based on the C57BL/6J background and carrying both human APP Swedish (K670N/M671L) and PS1-dE9 (deletion of exon 9), is a classic Alzheimer’s disease model. It closely recapitulates Aβ production, aggregation, and plaque formation in the brain, and is widely used for studying AD pathogenesis, screening Aβ‑targeted therapeutics, and conducting preclinical efficacy evaluations.

With aging, this model exhibits prominent extracellular Aβ deposition and senile plaques in the brain at 4–6 months of age, accompanied by progressively worsening microglial and astrocytic activation, synaptic protein loss, and cognitive impairment. Its pathological course closely resembles that of familial Alzheimer’s disease (AD) in humans; however, in the complete model, significant tau neurofibrillary tangles and substantial neuronal loss typically do not occur.

Product Advantages

Classic Aβ Cascade Model

The timing of plaque formation can be precisely predicted, faithfully recapitulating the cascade of damage involving Aβ oligomer toxicity, plaque accumulation, and neuroinflammation, making it a standard model for elucidating the core mechanisms of Aβ pathology.

Genetic background is stable

Maintained in a hemizygous state on a C57BL/6J background, the model exhibits excellent experimental reproducibility and allows direct comparison with extensive wild-type C57BL/6 databases and littermate controls, ensuring high data comparability.

Strong targeting specificity in applications

It is specifically designed for research in areas such as Alzheimer’s disease, cerebral amyloid angiopathy, neuroinflammation, synaptic plasticity impairment, and cognitive-behavioral disorders, and is particularly well suited for evaluating targeted therapies including Aβ antibodies, BACE1 inhibitors, and γ‑secretase modulators.

Outstanding value in translational medicine

It is the gold-standard model for developing Aβ-PET tracers, assessing drug distribution in the brain, and conducting preclinical proof-of-concept studies for immunotherapy, effectively bridging basic research with clinical phenotypes.

Data parameters

Strain Name

B6-Tg(APPswe,PSEN1dE9)85Dbo
Targeted gene

APP, PSEN1
Mutation site

APP: Swedish mutation (K670N/M671L); PSEN1: dE9 mutation (Exon 9 deletion)
Types of gene editing

Tg(APPswe,PSEN1dE9)85Dbo
genetic background

(C57BL/6J X C3H/HeJ) F2
Microbial Grade

SPF grade

Validation Data

The CNS consists of billions of neurons and serves as the structural basis for information transmission between them. Both Mo/HuAPP695swe and PS1-dE9 target CNS neurons. The humanized Mo/HuAPP695swe transgene enables mice to secrete human A-β peptides. Both the transgenic peptides and the full-length protein can be detected by antibodies specific to the human sequence in that region. The transgenic mutant human presenilin protein (PS1-dE9) replaces detectable endogenous mouse protein at high levels and is also immunodetected in whole-brain protein lysates.

During aging, the brains of APP/PS1 mice develop amyloid plaques and exhibit declines in cognitive and behavioral functions, along with other AD‑related pathological changes. The key features include the emergence of abnormal amyloid plaques in the brain as the mice age, cognitive impairment manifested by reduced learning and memory abilities, and observable neuronal degeneration and synaptic damage, including decreased synaptic density and neuronal loss.

 

 

Physiological characteristic changes (body weight, age/gender differences)

Body weight differences in mice with increasing age

Studies have found that, under conditions of identical genotype and age, female mice—except for 8-month-old APP/PS1 double-transgenic mice—weigh less than males. When comparing mice of the same age but different genotypes, except for 14-month-old APP/PS1 double-transgenic mice, the remaining mice maintained relatively stable body weights as they aged, with no significant differences observed. The maximum body weight difference among the APP/PS1 double-transgenic mice was approximately 7 g, and all mice weighed more than 20 g but did not exceed 40 g.

 

 

Effect of age and sex on body weight in AD mice; image source [3]

Behavioral science: Cognitive function declines with age (water maze test)

The difference in the decline of cognitive abilities between APP/PS1 double-transgenic mice narrows with increasing age, and aging itself contributes to cognitive impairment. Compared with 6-month-old mice, 14-month-old APP/PS1 mice show an increase of approximately 20 seconds; at 6 months, their escape latency can be up to 19 seconds longer than that of wild-type mice, and the number of platform crossings decreases significantly with age.

 

 

Morris water maze spatial exploration experiment; image source [3]

Under the same phenotypic conditions, comparison of male and female mice revealed that APP/PS1 double-transgenic males crossed the platform slightly more often than females. Increasing age also reduced both the escape latency and the number of platform crossings in both sexes, but no significant differences were observed between males and females.

 

 

Sex differences in water maze spatial exploration experiments in mice; image source [3]

 

Changes in Molecular and Pathological Indicators

01. Levels of Aβ protein deposition in the mouse hippocampus (by month of age and sex)

ELISA assay results showed that, with increasing age, the levels of Aβ40 and Aβ42 in the hippocampus of APP/PS1 double-transgenic mice gradually increased, reaching a highly significant elevation between 6 and 12 months of age.

At 6 months of age, the APP/PS1 group exhibited relatively lower levels of Aβ40 and Aβ42 deposition compared to other ages; consequently, the Aβ42/Aβ40 ratio was elevated relative to the other age groups. Starting at 8 months of age, this ratio increased with advancing age, and by 14 months, it had risen by an additional 4% in APP/PS1 double-transgenic mice compared to the 8-month-old cohort.

As the mice aged, Aβ40 and Aβ42 deposition in the hippocampus of APP/PS1 double-transgenic mice increased, and the Aβ42/Aβ40 ratio gradually rose. Compared with 6 months of age, the differences in hippocampal Aβ40, Aβ42, and the Aβ42/Aβ40 ratio at 14 months of age were statistically significant (P=0.003).

 

 

Effect of chronological age on Aβ production in the hippocampus of the AD group; image source [3]

In APP/PS1 double-transgenic female and male mice, hippocampal Aβ40, Aβ42, and the Aβ42/Aβ40 ratio all increased with age. Comparison between female and male APP/PS1 double-transgenic mice revealed no significant differences; Aβ40 and Aβ42 levels, as well as the Aβ42/Aβ40 ratio, were similar in both sexes.

 

 

As chronological age increases, sex influences Aβ production in the hippocampus of the AD group; image source [3].

 

02. Telomere length (TL) in multiple tissues shortens with age (age, sex)

Experimental measurements determined cellular telomere length (TL) in six mouse organs or tissues, including the prefrontal cortex, pituitary gland, hippocampus, and cerebellum in neural tissue; abdominal skin in epithelial tissue; and colon, a multi-tissue structure. The TL assay results showed that, in APP/PS1 double-transgenic mice, changes in cellular TL across these six organs or tissues were accompanied by shortening with increasing age.

 

 

The effect of increasing age on TL in AD mice; image source [3]

Under different sex conditions, the effect of increasing postnatal age on telomere length (TL) in various tissues of AD mice indicates that, for the same phenotype, female mice have shorter TLs in four brain cell types—prefrontal cortex, pituitary gland, hippocampus, and cerebellum—than male mice.

 

 

The effects of age and sex differences on TL in AD mice; image source: [3]

 

03. Incidence of bone marrow genetic damage MNPCE

When using the MNPCE assay to assess the overall level of genetic damage in AD mice, it was found that, in both the WT and AD groups, the frequency of micronucleated polychromatic erythrocytes (MNPCE) in bone marrow increased with age.

 

 

The effect of increasing age on MNPCE in AD mice and sex differences; image source [3]

 

04. Temporal changes in brain pathology (glial proliferation, amyloid plaques)

APP/PS1 microglial activation occurs prior to amyloid plaque deposition; microglial activation is observed in 3-month-old mice and further increases at 4 and 6 months of age. Amyloid plaques in the cerebral cortex begin to appear around 4 months of age, while in the hippocampus they emerge around 6 months of age, with plaque burden increasing with age.

 

 

 

 

Gliosis responding to Aβ in the brains of APP/PS1 mice; image source: [1]

 

05. Neural Damage: Neuronal Loss and Synaptic Injury

Neuronal degeneration and synaptic damage, including reduced synaptic density and neuronal loss, can also be observed in the brains of APP/PS1 mice. Neuronal loss begins to occur in the mice at 8 months of age.

 

 

Comparison of the morphology of OB neurons in APP/PS1 and WT mice; image source [5]

Application areas

● Mechanism of amyloid plaque formation: APP/PS1 mice can be used to study the formation of amyloid plaques, the metabolism and aggregation mechanisms of β-amyloid protein, and intervention strategies involving relevant drugs.
● Research on Cognitive and Behavioral Functions: Behavioral tests can assess changes in learning, memory, and cognitive function in APP/PS1 mice, thereby facilitating research into the pathogenesis of AD and potential therapeutic approaches.
● Research on Neurodegeneration and Synaptic Damage: APP/PS1 mice can be used to study the mechanisms of neuronal degeneration and synaptic damage in AD, as well as to evaluate neuroprotective strategies.

Breeding Techniques and Precautions

Strictly control inbreeding systems to avoid genetic differences.

 

APP/PS1 mice are aggressive and require close monitoring during housing. If fighting occurs among cage mates, separate the disputing individuals. In cases of severe aggression resulting in bite wounds, treat the injuries with povidone-iodine or an antibiotic ointment.

 

Strictly control environmental stimuli to reduce experimental stress.

 

Disinfectable toys can be placed in the cage to reduce the likelihood of mice fighting.

Literature support

Scientific literature published by Aniphe customers using this model is supported for SCI publication. (Link to the original paper)
1. Neuropharmacology.  2024 Nov 1;258:110090.
2.Peptides.  2024 Sep;179:171271.
3. Biochim Biophys Acta Mol Basis Dis.  2024 Oct;1870(7):167288.
4. J Neuroinflammation.  2024 Sep 3;21(1):218. 

Frequently Asked Questions

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Q1. Compared with the 5×FAD mice, what are the rationale and trade-offs underlying the choice of the APP/PS1 model?

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A: Both are widely used Aβ pathology models, but they differ significantly:
APP/PS1: Exhibits a relatively mild disease progression and a prolonged survival period (up to 18 months of age), making it well suited for evaluating drug efficacy when a longer therapeutic window is required, as well as for investigating underlying mechanisms on a timescale that closely approximates that of sporadic Alzheimer’s disease.
5×FAD: Carrying five familial AD mutations, this model exhibits rapid Aβ deposition (detectable as early as 1.5–2 months of age), an aggressive phenotype, and a high propensity for early neuronal loss and severe cognitive deficits. It is well suited for rapid screening; however, some findings may be overly dependent on high‑burden pathology, so its translational relevance should be interpreted with caution.
Rationale for selection: When a prophylactic or therapeutic window needs to be reserved, long-term administration is required, or comorbidities in the elderly need to be monitored, APP/PS1 is the preferred model; for rapid phenotypic screening or when high Aβ burden is desired, 5×FAD may be considered.

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Q2. What should be used as the control in this model? Why can’t we simply use wild-type littermates?

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A: The standard control is a non-transgenic (WT) mouse from the same litter (i.e., a negative control mouse born in the same litter as the APP/PS1 heterozygotes), and it is recommended to also include age-matched C57BL/6J wild-type mice as a background reference. Reason:
Littermate wild-type mice can control for differences in genetic background and maternal environment.
Because the APP/PS1 mice are maintained as hemizygotes, approximately 50% of the offspring are transgenic-positive and 50% are negative; wild-type littermates are readily available, eliminating the need for additional purchases.
Using only the standard C57BL/6J strain may overlook non-specific effects arising from the transgene insertion site or vector sequences.

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