Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: JU.Tg(NSE-APP751)Cordell
Genetic Background: JU (Developed by Eric Bradford at University of California, Davis)
This model was the first reported APP transgenic mouse. It overexpressed the human APP751 isoform, which includes the Kunitz serine protease inhibitor domain. The transgene was expressed throughout the brain from a rat neural-specific enolase (NSE) promoter; expression levels varied between substrains.
Deposits of extracellular Aβ were most frequent in the hippocampus and cortex and occasionally in the thalamus and striatum. Deposits stained positive for Aβ42. The majority of the Aβ deposits were diffuse, with a cotton-like appearance, and while dense deposits were occasionally observed, classic mature plaques were not seen (Higgins et al., 1994). Aβ immunoreactivity correlated with gene dosage; mice homozygous for the NSE-APP751 transgene had approximately double the number of Aβ deposits compared to heterozygous animals (Higgins et al., 1995). The mice developed abnormal tau immunoreactivity as detected with the Alz-50 antibody, which occasionally highlighted structures similar to dystrophic neurites and swollen boutons. Classic neurofibrillary tangles were not observed. Abnormal tau staining was highly associated with regions containing amyloid deposits. Aβ deposits and tau immunoreactivity both increased with age, roughly doubling between the age of two to three months and 22 months. Gliosis was observed in one instance of a 22-month-old mouse with extensive amyloid pathology.
Deficits in learning and memory appeared as the mice aged. At six months the mice performed similarly to wild-type controls, whereas at 12 months they demonstrated impaired learning and memory while performing tasks in a Y maze and a water maze (Moran et al., 1995).
The transgene expresses the wild-type human APP751 isoform under the control of the rat neural-specific enolase (NSE) promoter.
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
Aβ deposits were observed as early as two months of age. These deposits were diffuse and extracellular and had a “cotton-like” appearance. Classic mature plaques were not observed.
Classic tangles were not observed, but aberrant tau immunoreactivity was observed as early as two months.
Cell death was not formally assessed, however, overt neuronal death was not seen.
Gliosis was noted in a single 22-month-old animal with extensive Aβ deposits (Higgins et al., 1994).
Changes in LTP/LTD
Deficits in spatial memory and learning appear as the mice age. At 12 months the mice demonstrate learning and memory deficits as measured by a water-maze task and in spontaneous alternation in a Y maze (Moran et al., 1995). At six months cognition is largely normal.
Last Updated: 02 Dec 2016
- Higgins LS, Holtzman DM, Rabin J, Mobley WC, Cordell B. Transgenic mouse brain histopathology resembles early Alzheimer's disease. Ann Neurol. 1994 May;35(5):598-607. PubMed.
- Higgins LS, Rodems JM, Catalano R, Quon D, Cordell B. Early Alzheimer disease-like histopathology increases in frequency with age in mice transgenic for beta-APP751. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4402-6. PubMed.
- Moran PM, Higgins LS, Cordell B, Moser PC. Age-related learning deficits in transgenic mice expressing the 751-amino acid isoform of human beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5341-5. PubMed.
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