The APP/PS1 (also written as APP/PS1 or APP+PS1) double transgenic mouse model is one of the most established and widely used animal models for Alzheimer's disease (AD) research. It expresses mutant forms of both the [amyloid precursor protein (APP)](/genes/app) and [presenilin 1 (PSEN1](/genes/psen1)) genes, leading to progressive amyloid-beta (Aβ) deposition.
Genetic Design
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The APP/PS1 (also written as APP/PS1 or APP+PS1) double transgenic mouse model is one of the most established and widely used animal models for Alzheimer's disease (AD) research. It expresses mutant forms of both the [amyloid precursor protein (APP)](/genes/app) and [presenilin 1 (PSEN1](/genes/psen1)) genes, leading to progressive amyloid-beta (Aβ) deposition.
Genetic Design
Mermaid diagram (expand to render)
The APP/PS1 model combines two familial AD mutations:
The Swedish mutation (APP Swedish) is located at the beta-secretase cleavage site and dramatically increases total Abeta production. The PSEN1 M146L mutation alters gamma-secretase activity to favor production of the longer, more aggregation-prone Abeta42 species.
Mechanism of Pathology
Amyloid Generation Cascade
Increased Substrate: The Swedish mutation creates an optimal β-secretase cleavage site, increasing APP processing by BACE1
Altered γ-Cleavage: The PSEN1 M146L mutation shifts γ-secretase cleavage toward Aβ42, elevating the Aβ42/Aβ40 ratio
Nucleation and Aggregation: Elevated Aβ42 levels exceed the critical concentration for nucleation, leading to plaque formation
Temporal Progression
2-4 months: No significant pathology, baseline behavior
6 months: Initial plaque deposits appear in cortex
9-12 months: Extensive plaque burden in cortex and hippocampus
12+ months: Declining cognitive function, synaptic loss
No neuronal loss: Significant neuronal loss not observed despite plaque burden
Limited gliosis: Less pronounced neuroinflammation than some models
Comparison to Other Models
| Model | Plaque Onset | Tau Pathology | Neuronal Loss | Complexity | |-------|--------------|---------------|---------------|------------| | APP/PS1 | 6 months | Minimal | Limited | Dual transgenic | | 5xFAD | 2 months | Minimal | Some | 5 mutations | | 3xTg-AD | 6-12 months | Yes (by 12mo) | Yes | Triple transgenic | | APPDutch | 12+ months | No | No | Single mutation |
Related Pages
[5xFAD Transgenic Model](/models/5xfad-transgenic-mouse-model) — More aggressive amyloid model
[3xTG-AD](/mechanisms/3xtg-ad-mouse) — Triple transgenic with both amyloid and tau
[BACE1 inhibitors](/therapeutics/bace1-inhibitors) — Therapeutic target tested in this model
References
[Jankord et al., 2007 - APP/PS1 mice as a model for AD](https://doi.org/10.1016/j.neurobiolaging.2006.06.019)
[Mullan et al., 1992 - Swedish APP mutation](https://doi.org/10.1038/359722a0)
[Duff et al., 1996 - PSEN1 mutations and APP/PS1 model development](https://doi.org/10.1038/379060a0)
[Sterniczuk et al., 2010 - Antemortem cognitive testing in APP/PS1 mice](https://doi.org/10.1016/j.jneumeth.2010.06.018)
Pathway Diagram
The following diagram shows the key molecular relationships involving APP/PS1 Dual Transgenic Mouse Model discovered through SciDEX knowledge graph analysis: