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.
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, 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
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
Web site: http://www.kuleuven.ac.be/lrd
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.
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.