Research Models

APP(V717I) x PS1(A246E)

Synonyms: APPxPS1, APP(V717I)x PS1(A246E), APP[V717I]x PS1[A246E], APP.V717I x PS1.A246E

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Species: Mouse
Genes: APP, PSEN1
Mutations: APP V717I (London), PSEN1 A246E
Modification: APP: Multi-transgene; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease, Cerebral Amyloid Angiopathy
Strain Name: Thy1-hAPP.V717I ( C57BL/6)x Thy1-hPS1.A246E (FVB/N)
Genetic Background: Originally generated on FVB/N background; available at reMYND as C57BL/6xFVB/N
Availability: Available through reMYND.

Summary

These are bigenic mice that overexpress both mutant APP (V717I mutation) and mutant PSEN1 (A246E mutation). They were first generated and described by the laboratory of Fred Van Leuven (Dewachter et al., 2000). The transgenes are coexpressed in the same cells, mainly neurons. The neuropathology in these mice is more severe than is observed in either of the parental single transgenic lines. Compared with APP(V717I) mice, overexpression of both transgenes leads to more aggressive amyloidosis; the PS1(A246E) single transgenic does not develop amyloid pathology. The double transgenic mice also have elevated Aβ levels compared with the APP(V717I) single transgenic, especially Aβ42, resulting in an approximately 10-fold increase in the Aβ42/Aβ40 ratio in double transgenic mice. In general, APP models containing the London mutation are thought to be especially suitable for testing BACE inhibitors and modulators as the mutation is situated away from the β-cleavage site.

Neuropathology

Soluble, oligomeric Aβ at two months which increases with age. Amyloid plaques at six to nine months, which is earlier than APP(V717I) single transgenics. Plaques start in the subiculum and spread to the frontal cortex. Amyloid-associated inflammation. CAA pathology at eight months; microbleeds at 12-15 months. Dystropic neurites containing hyperphosphorylated tau, but no tangle pathology.

Cognition/Behavior

From the age of five months spatial and non-spatial orientation and memory deficits by Morris Water Maze are observed. Impaired associative learning, hyperactivity, anxiety, and aggression.

Modification Details

Double transgenic mice were generated by crossing mice overexpressing human APP with the London mutation to those overexpressing human PSEN1 with the A246E mutation. Both transgenes are driven by the Thy1 promoter.

Availability

Available through the contract research organization reMYND (CRO@remynd.com).

Phenotype Timeline

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Observed

Absent

  • Tangles

Unknown

Plaques

Plaques start in cortex, hippocampus and subiculum at 4-6 months.

Tangles

Dystrophic neurites containing hyperphosphorylated murine tau, but no tangle pathology.

Gliosis

Elevated GFAP, microglial activation, and other markers of brain inflammation increase as of 4.5 months.

Changes in LTP/LTD

Significant deficit in LTP in CA1 region of the hippocampus at 6 months.

Cognitive Impairment

From the age of 5 months, spatial and non-spatial orientation and memory deficits by Morris water maze and other tests. Also deficits in associative learning.

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References

Research Models Citations

  1. PS1(A246E)
  2. APP(V717I)

Paper Citations

  1. . 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.

External Citations

  1. reMYND

Further Reading

Papers

  1. . Pathological Hallmarks, Clinical Parallels, and Value for Drug Testing in Alzheimer's Disease of the APP[V717I] London Transgenic Mouse Model. Int J Alzheimers Dis. 2010;2010 PubMed.
  2. . 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.
  3. . Capacitive calcium entry is directly attenuated by mutant presenilin-1, independent of the expression of the amyloid precursor protein. J Biol Chem. 2003 Jan 24;278(4):2484-9. PubMed.
  4. . Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J Biol Chem. 1999 Mar 5;274(10):6483-92. PubMed.
  5. . Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the london mutant of human APP in neurons. Am J Pathol. 2000 Oct;157(4):1283-98. PubMed.
  6. . Neuronal deficiency of presenilin 1 inhibits amyloid plaque formation and corrects hippocampal long-term potentiation but not a cognitive defect of amyloid precursor protein [V717I] transgenic mice. J Neurosci. 2002 May 1;22(9):3445-53. PubMed.