Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: C57BL6
Availability: Available through Thomas Bayer.
The TBA42 model was designed to produce and secrete an N-terminally truncated Aβ peptide. TBA42, which stands for truncated beta-amyloid 42, specifically encodes an Aβ3–42 peptide with a glutamine substituted for the naturally occurring glutamate at position 3 of Aβ in order to facilitate pyroglutamate formation in vivo. Pyroglutamate Aβ3–42 (AβpE3–42) is a modified Aβ peptide that is enriched in the AD brain. It is derived from Aβ42, from which the first two amino acids are removed, and the resulting free amino group is converted to a cyclic amide by the enzyme glutaminyl cyclase. This creates a highly stable, neurotoxic form of Aβ that aggregates faster than conventional full-length Aβ42. In addition, pyroglutamate Aβ has been identified as a major component of Aβ plaques (Saido et al., 1995; Harigaya et al., 2000). The strategy used to generate this model enables the effects of this specific Aβ species to be assessed while avoiding the potential confounds of over-expressing APP.
TBA42 mice exhibit intraneuronal accumulation of Aβ in the hippocampus by three months and in cerebellar nuclei by six months. Amyloid plaques are only very rarely detected, but marked gliosis in the hippocampus occurs by 12 months.
Behaviorally, the mice exhibit select age-dependent deficits, including a deficit in working memory as assessed by the cross maze at 12 months, but not at three and six months. They also have an early and persistent decrease in anxiety as measured by the elevated plus maze. General motor coordination is comparable to wild-type mice at three and six months as indicated by the balance beam test, but impairments are observed at 12 months.
When crossed with the 5xFAD model, the resulting progeny, known as FAD42 mice, have an aggravated behavioral phenotype compared with either 5xFAD or TBA42 alone. Specifically, FAD42 mice have greater motor impairment on the balance beam and reduced anxiety in the elevated plus maze (Wittnam et al., 2012).
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Neuronal Loss
- Synaptic Loss
- Changes in LTP/LTD
Very rare extracellular Aβ deposits at all ages tested.
Marked gliosis in the hippocampus as measured by GFAP staining at 12 months.
Changes in LTP/LTD
Age-dependent behavioral deficits, including working memory as assessed by the cross maze at 12 months, but not at 3 and 6 months.
Research Models Citations
- Saido TC, Iwatsubo T, Mann DM, Shimada H, Ihara Y, Kawashima S. Dominant and differential deposition of distinct beta-amyloid peptide species, A beta N3(pE), in senile plaques. Neuron. 1995 Feb;14(2):457-66. PubMed.
- Harigaya Y, Saido TC, Eckman CB, Prada CM, Shoji M, Younkin SG. Amyloid beta protein starting pyroglutamate at position 3 is a major component of the amyloid deposits in the Alzheimer's disease brain. Biochem Biophys Res Commun. 2000 Sep 24;276(2):422-7. PubMed.
- Wittnam JL, Portelius E, Zetterberg H, Gustavsson MK, Schilling S, Koch B, Demuth HU, Blennow K, Wirths O, Bayer TA. Pyroglutamate amyloid β (Aβ) aggravates behavioral deficits in transgenic amyloid mouse model for Alzheimer disease. J Biol Chem. 2012 Mar 9;287(11):8154-62. PubMed.
- Yang H, Wittnam JL, Zubarev RA, Bayer TA. Shotgun brain proteomics reveals early molecular signature in presymptomatic mouse model of Alzheimer's disease. J Alzheimers Dis. 2013 Jan 1;37(2):297-308. PubMed.