Species: Mouse
Genes: PSEN1
Mutations: PSEN1 A246E
Modification: PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: Tg(Thy1-PSEN1*A246E)2Vln/0
Genetic Background: FVB/N
Availability: No longer available through Paul van Dun

Summary

These transgenic mice overexpress human PSEN1 with the A246E mutation, which is associated with familial early-onset Alzheimer’s disease. Human PSEN1 is expressed at levels similar to endogenous murine PSEN1. In humans this mutation is associated with severe neuropathology, but histological analysis of the transgenic mouse brain revealed no major abnormalities up to two years of age. Likewise, learning and spatial memory were unaffected in the water maze test. These mice have been used to generate several lines of bigenic animals including APP(V717I) x PS1(A246E). Bigenic animals have elevated Aβ and amyloid in brain parenchyma and cerebral blood vessels (Dewachter et al., 2000).

Modification Details

Transgene containing human PSEN1 with the A246E mutation driven by the mouse Thy1 promoter.

Neuropathology

Histologically normal up to two years old by hematoxylin-eosin, silver, and thioflavin-S staining (Schneider et al., 2001).

Cognition/Behavior

Learning and spatial memory unaffected as assessed by the water maze test. Neither the escape latency nor escape pathway was different from PSEN1 wild-type mice at one and nine months of age (Schneider et al., 2001).

Other Phenotypes

Mice are more sensitive to kainic acid displaying greater KA-induced seizure activity and neuronal damage. LTP induced by a strong stimulus was not altered, but a weak stimulation at synapses between Schaeffer’s collaterals and CA1 pyramidal neurons elicited LTP only in mutant mice (Schneider et al., 2001).

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References

Research Models Citations

1. APP(V717I) x PS1(A246E)

Paper Citations

1. Dewachter I, Van Dorpe J, Smeijers L, Gilis M, Kuipéri C, Laenen I, Caluwaerts N, Moechars D, Checler F, Vanderstichele H, Van Leuven F. Aging increased amyloid peptide and caused amyloid plaques in brain of old APP/V717I transgenic mice by a different mechanism than mutant presenilin1. J Neurosci. 2000 Sep 1;20(17):6452-8. PubMed.
2. Schneider I, Reverse D, Dewachter I, Ris L, Caluwaerts N, Kuiperi C, Gilis M, Geerts H, Kretzschmar H, Godaux E, Moechars D, Van Leuven F, Herms J. Mutant presenilins disturb neuronal calcium homeostasis in the brain of transgenic mice, decreasing the threshold for excitotoxicity and facilitating long-term potentiation. J Biol Chem. 2001 Apr 13;276(15):11539-44. PubMed.

Further Reading