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
Double transgenic mice 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.
Soluble, oligomeric Aβ at two months which increases with age. Amyloid plaques at 6-9 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.
From the age of five months spatial and non-spatial orientation and memory deficits by Morris Water Maze. Impaired associative learning, hyperactivity, anxiety, and aggression.
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). 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 the 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 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.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
Plaques start in cortex, hippocampus and subiculum at 4-6 months.
Dystrophic neurites containing hyperphosphorylated murine tau, but no tangle pathology.
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.
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.
Research Models Citations
- 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.
- Tanghe A, Termont A, Merchiers P, Schilling S, Demuth HU, Scrocchi L, Van Leuven F, Griffioen G, Van Dooren T. 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.
- 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.
- Herms J, Schneider I, Dewachter I, Caluwaerts N, Kretzschmar H, Van Leuven F. 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.
- Moechars D, Dewachter I, Lorent K, Reversé D, Baekelandt V, Naidu A, Tesseur I, Spittaels K, Haute CV, Checler F, Godaux E, Cordell B, Van Leuven F. 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.
- Van Dorpe J, Smeijers L, Dewachter I, Nuyens D, Spittaels K, Van den Haute C, Mercken M, Moechars D, Laenen I, Kuiperi C, Bruynseels K, Tesseur I, Loos R, Vanderstichele H, Checler F, Sciot R, Van Leuven F. 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.
- Dewachter I, Reversé D, Caluwaerts N, Ris L, Kuipéri C, Van den Haute C, Spittaels K, Umans L, Serneels L, Thiry E, Moechars D, Mercken M, Godaux E, Van Leuven F. 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.