Research Models
Tg4-42
Synonyms: Tg-Aβ(4-42)
Species: Mouse
Genes: APP
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: C57BL6
Availability: Available through Thomas Bayer.
Summary
The Tg4-42 model was engineered to produce the peptide Aβ4-42, one of a variety of N-terminally truncated Aβ species identified in the AD brain. The Aβ4-42 peptide, which begins with a phenylalanine at position 4, may be a particularly abundant form of N-truncated Aβ in the human brain (Masters et al., 1985; Lewis et al., 2006; Portelius et al., 2010). The genetic construct contains the Aβ4-42 sequence fused to the murine thyrotropin-releasing hormone (TRH) signal peptide under the control of the Thy1 promoter, which allows the Aβ to be secreted extracellularly in a neuron-specific manner. Transgene expression is highest in the hippocampus, predominantly in the CA1 region, and is detectable starting around two months of age. The transgene is also expressed in occipital cortex, piriform cortex, striatum, and superior colliculus. The Tg4-42 model does not express human APP; therefore, the effects of the Aβ4-42 peptide are not confounded by APP or other cleavage products.
The Tg4–42 model does not develop extracellular amyloid plaques; however, the secreted Aβ4-42 readily forms soluble, neurotoxic aggregates. Tg4-42 mice develop age- and dose-dependent hippocampal neuronal loss in the CA1 region, as well as inflammation as indicated by microgliosis and astrogliosis.
Behaviorally, these mice show an age-dependent spatial learning deficit as indicated by the Morris water maze. This deficit is not observed at three months, but develops by eight months in homozygous animals and by 12 months in heterozygous animals (Bouter et al., 2013).
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+.
Absent
- Plaques
- Tangles
No Data
- Changes in LTP/LTD
Plaques
Absent.
Tangles
Absent.
Neuronal Loss
Age- and dose-dependent neuronal loss in the hippocampus CA1 region of hemizygous and homozygous mice. Compared with wild-type, hemizygous mice had 38% neuronal loss at 8 months, and 49% loss at 12 months. No difference at 3 months.
Gliosis
Reactive microglia and astrocytes in the hippocampus starting at 2 months.
Synaptic Loss
Altered synaptophysin staining in the CA3 region of the hippocampus. More pronounced in homozygous mice than hemizygous mice at 8 months.
Changes in LTP/LTD
Unknown.
Cognitive Impairment
Spatial reference memory is impaired as assessed by Morris water maze at 8 months in homozygous mice and 12 months in hemizygous mice. Deficit is age-dependent and is not detected at 3 months. Impaired contextual fear conditioning at 12 months.
Last Updated: 07 Apr 2022
References
Paper Citations
- Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A. 1985 Jun;82(12):4245-9. PubMed.
- Lewis H, Beher D, Cookson N, Oakley A, Piggott M, Morris CM, Jaros E, Perry R, Ince P, Kenny RA, Ballard CG, Shearman MS, Kalaria RN. Quantification of Alzheimer pathology in ageing and dementia: age-related accumulation of amyloid-beta(42) peptide in vascular dementia. Neuropathol Appl Neurobiol. 2006 Apr;32(2):103-18. PubMed.
- Portelius E, Bogdanovic N, Gustavsson MK, Volkmann I, Brinkmalm G, Zetterberg H, Winblad B, Blennow K. Mass spectrometric characterization of brain amyloid beta isoform signatures in familial and sporadic Alzheimer's disease. Acta Neuropathol. 2010 Aug;120(2):185-93. PubMed.
- Bouter Y, Dietrich K, Wittnam JL, Rezaei-Ghaleh N, Pillot T, Papot-Couturier S, Lefebvre T, Sprenger F, Wirths O, Zweckstetter M, Bayer TA. N-truncated amyloid β (Aβ) 4-42 forms stable aggregates and induces acute and long-lasting behavioral deficits. Acta Neuropathol. 2013 Aug;126(2):189-205. PubMed.
Other Citations
Further Reading
No Available Further Reading
COMMENTS / QUESTIONS
University of Goettingen
The Tg4-42 model is the first, and currently only, model to express N-truncated human Aβ4-42 without any other mutation, yet still develop neuronal loss and behavioral deficits. This is unique, because all other transgenic models that develop these pathologies have at least one mutation. Likewise, the TBA42 model, which has glutamine in place of glutamate at position three of Aβ, develops similar pathologies while expressing otherwise wild-type Aβ. The Tg4-42 model has very clear hippocampal pathology with severe age-dependent neuron loss, as determined by stereology, and it exhibits age-dependent cognitive decline.
Researchers interested in the molecular network of the hippocampus and its molecular signature related to AD might find this model of interest. It is known that APP and its proteolytic products, such as sAPPα, sAPPβ, p3, and C-terminal fragments, have biological effects, including neurotrophic and synaptothrophic effects. Because the Tg4-42 model expresses only human Aβ4-42, the effects of this peptide can be studied without interference from other human APP products. Another advantage is that this model does not develop plaques, which are not correlated with cognitive decline in AD patients.
A major problem with APP transgenic models of AD is that they depend on mutant APP expression. Each mutation has a particular effect on Aβ production. It could very well be that these models only reflect a subset of AD patients. It is now well-recognized that N-truncated Aβ species (including 4-42) are abundant in the AD brain, including in sporadic cases, but they are rare in most APP transgenic mice.
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