The 5xFAD transgenic mouse model is one of the most widely used animal models for Alzheimer's disease (AD) research. This model co-expresses five familial AD mutations—three in the [amyloid precursor protein (APP)](/genes/app) gene and two in the [presenilin 1 (PSEN1)](/genes/psen1) gene—under the neural-specific Thy1 promoter, leading to aggressive amyloid-beta (Aβ) pathology.
Genetic Background
The 5xFAD model carries the following familial AD mutations:
The "5x" designation refers to the five total mutations, and "FAD" denotes familial Alzheimer's disease.
Mechanism of Pathology
Amyloid Precursor Protein Processing
The model overexpresses APP containing the Swedish, Florida, and London mutations, leading to:
Increased Aβ Production: The Swedish double mutation at the β-secretase cleavage site dramatically increases the rate of Aβ generation by facilitating β-secretase (BACE1) access to APP.
Altered Aβ Peptide Profile: The mutations shift γ-secretase cleavage toward the more aggregation-prone [Aβ42](/mechanisms/amyloid-cascade) species.
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The 5xFAD transgenic mouse model is one of the most widely used animal models for Alzheimer's disease (AD) research. This model co-expresses five familial AD mutations—three in the [amyloid precursor protein (APP)](/genes/app) gene and two in the [presenilin 1 (PSEN1)](/genes/psen1) gene—under the neural-specific Thy1 promoter, leading to aggressive amyloid-beta (Aβ) pathology.
Genetic Background
The 5xFAD model carries the following familial AD mutations:
The "5x" designation refers to the five total mutations, and "FAD" denotes familial Alzheimer's disease.
Mechanism of Pathology
Amyloid Precursor Protein Processing
The model overexpresses APP containing the Swedish, Florida, and London mutations, leading to:
Increased Aβ Production: The Swedish double mutation at the β-secretase cleavage site dramatically increases the rate of Aβ generation by facilitating β-secretase (BACE1) access to APP.
Altered Aβ Peptide Profile: The mutations shift γ-secretase cleavage toward the more aggregation-prone [Aβ42](/mechanisms/amyloid-cascade) species.
Accelerated Aggregation: The Florida and London mutations enhance Aβ42 aggregation kinetics, promoting rapid plaque formation.
Presenilin 1 Mutations
The two PSEN1 mutations (M146L, L286V) affect γ-secretase function:
Alter the cleavage site specificity, producing more Aβ42 relative to Aβ40
Lead to earlier onset and more severe pathology compared to single-mutation models
Pathological Features
Amyloid Plaque Formation
Plaques appear as early as 2 months of age in the cortex
By 4-6 months, extensive plaque deposition in the hippocampus and subiculum
Plaques are dense-core type, with the characteristic amyloid fibrillar structure
Neuronal Loss
Significant loss of [subcortical cholinergic neurons](/cell-types/basal-forebrain-cholinergic-neurons) by 9 months
Progressive neuronal atrophy in affected brain regions
Neuronal loss precedes or coincides with plaque deposition
No neuronal loss mechanism: Neuronal loss appears driven by plaque burden rather than soluble oligomers
Limited translational relevance: Aggressive amyloid pathology may not fully reflect sporadic AD
Related Models
[APP/PS1](/models/app-ps1-dual-transgenic-model) — Dual transgenic model with APP Swedish + PSEN1 M146L
[3xTg-AD](/models/3xtg-ad-mouse-model) — Triple transgenic model with both amyloid and tau pathology
[Trem2](/genes/trem2) knockout crosses — Used to study microglial contributions to amyloid clearance
References
[Oakley et al., 2006 - 5xFAD: A novel transgenic mouse model of AD with early amyloid deposition](https://doi.org/10.1016/j.neurobiolaging.2005.09.021)
[Mullan et al., 1992 - A novel Swedish APP mutation associated with familial AD](https://doi.org/10.1038/359722a0)
[Bandyopadhyay et al., 2020 - 5xFAD modeling of amyloid pathology in Alzheimer's disease](https://pubmed.ncbi.nlm.nih.gov/33257647/)
[Shin et al., 2017 - Characterization of the 5xFAD mouse model for Alzheimer's disease](https://doi.org/10.3233/JAD-170671)