Synonyms: Truncated beta-amyloid 42
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 overexpressing APP.
TBA42 mice display a progressive neurological phenotype that is characterized by memory and motor deficits as well as neurodegenerative changes in the brain. Amyloid plaques are only rarely detected, but Aβ accumulates within neurons of the hippocampus by 3 months of age and in cerebellar nuclei by 6 months. AβpE3–42 accumulates in the spinal cord and pyramidal neurons of the motor cortex. As they age, the mice develop neuronal loss in the CA1 region of the hippocampus. Specifically, neuronal numbers are comparable to wild-type at 3 and 6 months of age, but by 12 months of age there is a 35 percent loss. Gliosis occurs in the hippocampus by 12 months (Meißner et al., 2014; Wittnam et al., 2012).
Behaviorally, these mice exhibit age-dependent deficits in multiple tests of memory and motor skills. Working memory, as measured by the cross maze, is affected at 12 months, but not at 3 or 6 months of age. Spatial reference memory, as measured by the Morris water maze, is also impaired by 12 months of age. Sensory-motor deficits develop with age, including a reduction in locomotor activity and swimming speed, which may contribute to impaired performance in the maze tasks. General motor coordination is comparable to wild-type mice at 3 and 6 months of age, as indicated by the balance-beam test, but impairments are observed at 12 months. The mice also develop an age-dependent reduction in anxiety as reflected by greater time in the open arms of the elevated plus maze (Meißner et al., 2014; Wittnam et al., 2012).
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+.
- Synaptic Loss
- Changes in LTP/LTD
Very rare extracellular Aβ deposits.
Age-dependent neuronal loss in the CA1 region of the hippocampus. No difference from wild-type mice at 3 and 6 months of age, but approximately 35% loss at 12 months of age.
Marked gliosis in the hippocampus as measured by GFAP staining at 12 months.
Changes in LTP/LTD
Age-dependent deficits in working and spatial reference memory at 12 months, but not at 3 and 6 months.
Last Updated: 28 Apr 2014
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.
- Meißner JN, Bouter Y, Bayer TA. Neuron Loss and Behavioral Deficits in the TBA42 Mouse Model Expressing N-Truncated Pyroglutamate Amyloid-β3-42. J Alzheimers Dis. 2015;45(2):471-82. 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.
COMMENTS / QUESTIONS
University of Goettingen
The TBA42 model produces human pyroglutamate Aβ3-42 in the CA1 region of the hippocampus. This peptide has received considerable attention in recent years, and has been hypothesized to be the Aβ species that seeds toxic aggregates, having prion-like features. The TBA42 model specifically expresses N-truncated human Aβ3-42 fused to a thyrotropin-releasing hormone backbone. Because these animals express no human APP, the effects of pyroglutamate Aβ3-42 are not confounded by other human APP products, such as sAPPα, sAPPβ, p3, and C-terminal fragments, which have a variety of biological activities, including neurotrophic and synaptotrophic effects. Another advantage to the TBA42 model is that it does not develop a severe plaque load. (Plaque levels do not correlate with cognitive decline in AD patients).
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