Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: C57BL6
Availability: Available through Thomas Bayer. Research with this model is available from QPS Austria.
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).
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Changes in LTP/LTD
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.
Reactive microglia and astrocytes in the hippocampus starting at 2 months.
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
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.
- 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.
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