Research Models

PDAPP(line109)

Synonyms: hAPP695Indiana, elan mouse, PDAPP, PD-APP

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Species: Mouse
Genes: APP
Mutations: APP V717F (Indiana)
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: C57B6 x DBA2
Availability: Unknown

Summary

The PDAPP mouse was first described in 1995 (Games et al., 1995) and is considered one of the earliest mouse models of Alzheimer's disease. From a young age this model exhibits cognitive deficits in a variety of tasks, including spatial working memory at four months as assessed by the Morris water maze (Hartman et al., 2005). Deficits in recognition memory follow at approximately six months of age, as assessed by novel object recognition (Dodart et al., 1999). Many of the cognitive deficits in this model present prior to plaque deposition, which occurs at approximately six months of age.

As originally described, these mice exhibit high human APP expression, greater than 10-fold higher than endogenous murine APP. Because the construct allows for alternative splicing, multiple isoforms are produced including APP 695, 751 and 770. These mice exhibit extracellular Aβ deposition, dystrophic neurites, gliosis, and loss of synaptic and dendritic density in the hippocampus (Games et al., 1995).

Modification Details

A PDGF-driven human APP minigene with the V717F (Indiana) mutation. The construct contained APP introns 6-8 allowing alternative splicing of exons 7 and 8.

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

  • Tangles
  • Neuronal Loss

No Data

Plaques

In heterozygous mice no plaque pathology at 4-6 months. At 6-9 months mice begin to exhibit deposits of human Aβ in the hippocampus, corpus callosum, and cerebral cortex. Plaques become more extensive with age and vary in size and structure including diffuse irregular plaques and compact cored plaques (Games et al., 1995).

Tangles

No paired helical filaments or aggregates, but phosphorylated tau immunoreactivity is observed in dystrophic neurites after 14 months (Masliah et al., 2001).

Neuronal Loss

Absent.

Gliosis

GFAP-positive astrocytes and activated microglia associated with plaques (Games et al., 1995).

Synaptic Loss

Decreased synaptic density in the dentate gyrus as measured by synaptophysin immunoreactivity. Also decreased dendritic density as measured by MAP2 immunoreactivity (Games et al., 1995).

Changes in LTP/LTD

Alterations in LTP induced by theta burst stimulation at 4-5 months which is prior to plaque formation; although the potentiation immediately after TBS was comparable to control mice, the potentiation decayed more rapidly in PDAPP mice. Also paired pulse facilitation was enhanced. Responses to high frequency stimulation bursts were distorted (Larson et al., 1999).

Cognitive Impairment

Deficits in a variety of memory paradigms from a young age. Robust deficits in the radial arm maze at 3 months (deficits appear before amyloid plaque deposits). Object recognition, 6, 9-10 months. Operant learning, 3, 6 months (Dodart et al., 1999).

Last Updated: 31 Mar 2022

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References

Paper Citations

  1. Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F. Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature. 1995 Feb 9;373(6514):523-7. PubMed.
  2. Hartman RE, Izumi Y, Bales KR, Paul SM, Wozniak DF, Holtzman DM. Treatment with an amyloid-beta antibody ameliorates plaque load, learning deficits, and hippocampal long-term potentiation in a mouse model of Alzheimer's disease. J Neurosci. 2005 Jun 29;25(26):6213-20. PubMed.
  3. Dodart JC, Meziane H, Mathis C, Bales KR, Paul SM, Ungerer A. Behavioral disturbances in transgenic mice overexpressing the V717F beta-amyloid precursor protein. Behav Neurosci. 1999 Oct;113(5):982-90. PubMed.

Further Reading

News

  1. Vaccinating Against Plaques

Papers

  1. Webster SJ, Bachstetter AD, Nelson PT, Schmitt FA, Van Eldik LJ. Using mice to model Alzheimer's dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models. Front Genet. 2014;5:88. Epub 2014 Apr 23 PubMed.