General Information

Transgene: Human APP 770 cDNA

Mutation: Flemish A692G, Dutch E693Q

Promoter: Mouse thy-1 promoter

Mouse Strain: The constructs were microinjected into 1.5 day-old prenuclear embryos isolated from superovulated FVB/N females

In AD human patients:

--Dutch mutation causes HCHWA-D, characterized by extensive amyloid deposits in the small leptomenigeal and cortical arterioles, leads to premature death

--Flemish mutation causes a combined pathology of cerebral amyloid angiopathy (CAA) and presenile AD with the presence of both large-cored parenchymal senile plaques and extensive amyloid deposits in blood vessels.

Phenotype

Neuropathological Analysis:

Both APP/Fl and APP/Du transgenic mice significantly decrease a-secretase APP while increasing b-secretase cleaved C-terminal fragments, relative to wt APP transgene. (Mutations located near the a-secretase cleavage site favor b cleavage of APP. Increased processing of human APP at the b-secretase cleavage site causing increase formation of N-terminal fragments of Ab protein, which leads to amyloid plaque formation). 

Ab level in the APP/Fl and APP/Du mice remains low, without formation of amyloid plaque. In fact, these transgenic mice do not develop amyloid plaques or tau pathology, even by 22 months of age. 

Behavioral:

Behavioral, pharmacological and pathological observations disclose subtle aspects of early and late onset AD like APP/wt and APP/London, such as differential glutamatergic responses, increased aggression, occasional spontaneous seizures and variable premature death.

Availability

Licensing/academic distribution contact information:

Paul Van Dun
Director - KULeuvenR&D
Groot Begijnhof 59
B-3000 Leuven Belgium
tel +32 16 326508
fax +32 16 326515
Email: Paul.Vandun@lrd.kuleuven.ac.be
Web site: http://www.kuleuven.ac.be/lrd

Patents: None

Reference

Primary:

Kumar-Singh S, Dewachter I, Moechars D, Lubke U, De Jonghe C, Ceuterick C, Checler F, Naidu A, Cordell B, Cras P, Van Broeckhoven C, Van Leuven F.  Behavioral disturbances without amyloid deposits in mice overexpressing human amyloid precursor protein with Flemish (A692G) or Dutch (E693Q) mutation. Neurobiol Dis 2000 Feb;7(1):9-22. Abstract.

Associated:

Moechars D, Dewachter I, Lorent K, Reverse 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. Abstract.