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) and presenilin 1 (PSEN1) genes, leading to progressive amyloid-beta (Aβ) deposition.
The APP/PS1 model combines two familial AD mutations:
| Gene |
Mutation |
Promoter |
Expression Level |
| APP |
Swedish (K670N/M671L) |
Mouse Prion promoter |
~5-10x endogenous |
| PSEN1 |
M146L |
Mouse Prion promoter |
Endogenous levels |
The Swedish mutation (APP Swedish) is located at the β-secretase cleavage site and dramatically increases total Aβ production. The PSEN1 M146L mutation alters γ-secretase activity to favor production of the longer, more aggregation-prone Aβ42 species.
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Increased Substrate: The Swedish mutation creates an optimal β-secretase cleavage site, increasing APP processing by BACE1
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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
- 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
- Plaque distribution: Cortex, hippocampus (CA1, dentate gyrus), subiculum
- Plaque types: Both diffuse and dense-core plaques present
- Plaque morphology: Typical amyloid fibrillar structure on histology
- Vascular amyloid: Some CAA (cerebral amyloid angiopathy) in older mice
- Microgliosis: Activated microglia surrounding plaques, especially in cortex
- Astrocytes show reactive gliosis near plaque deposits
- Cytokine upregulation: IL-1β, TNF-α, IL-6 in plaque-rich regions
- Loss of synaptic markers (synaptophysin, PSD95) in hippocampus
- Impaired LTP (long-term potentiation) in hippocampal slices
- Reduced dendritic spine density in CA1 neurons
- Spatial memory impairments in Morris water maze (detectable at 9-12 months)
- Deficits in contextual fear conditioning
- Working memory deficits in radial arm maze
The APP/PS1 model is used to test:
- Immunotherapies: Active and passive anti-Aβ vaccination approaches
- Small molecule inhibitors: γ-secretase modulators, BACE1 inhibitors (historically)
- Aggregation inhibitors: Compounds targeting Aβ oligomerization
- Anti-inflammatory agents: Testing microglial modulation strategies
- CSF Aβ42 as pharmacodynamic biomarker
- PET amyloid imaging agent validation
- Plasma biomarker correlation with brain pathology
- Amyloid-triggered neuroinflammation pathways
- Synaptic dysfunction mechanisms
- Neuronal network hyperactivity in early AD
¶ Advantages and Limitations
- Moderate progression: Pathology develops over 6-12 months, allowing therapeutic intervention windows
- Well-characterized: Extensive background literature, standardized protocols
- Robust phenotype: Clear plaque pathology and behavioral deficits
- F1 hybrid background: C57BL6 x C3H background reduces background strain effects
- Amyloid-only: Lacks prominent tau pathology (neurofibrillary tangles)
- Overexpression artifact: Prion promoter drives non-physiological expression
- No neuronal loss: Significant neuronal loss not observed despite plaque burden
- Limited gliosis: Less pronounced neuroinflammation than some 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 |
- Jankord et al., 2007 - APP/PS1 mice as a model for AD
- Mullan et al., 1992 - Swedish APP mutation
- Duff et al., 1996 - PSEN1 mutations and APP/PS1 model development
- Sterniczuk et al., 2010 - Antemortem cognitive testing in APP/PS1 mice