Updated 30 October 2005
The PDGF-driven hAPP minigene represents a fusion product of the following:
hAPP cDNA spanning exon 1 through the XcmI site in exon 6 including 180
bp of exon 6;
- 166-bp PCR-generated fragment of genomic hAPP sequence extending from the XcmI
site in exon 6 to an engineered BamHI site in intron 6;
- 6.8-kb BamHI fragment of hAPP genomic DNA containing exons 7 and 8 and
extending from the BamHI site located 1658 bp upstream of exon 7 to the
first BamHI site of intron 8;
- 313-bp PCR-generated fragment of genomic hAPP sequence extending from an engineered
BamHI site to the XhoI site in exon 9; and
- hAPP cDNA sequence extending from the XhoI site in exon 9 to 135 bp downstream
of the first hAPP poly(A) signal in the hAPP 3`-untranslated region. The unique
XhoI site in hAPP intron 7 was destroyed.
Mutation: Human APP with valine
at residue 717 substituted by phenylalanine (APP V717F)
Promoter: human platelet derived growth factor b
(PDGF-b) chain gene promoter
Mouse Strain: C57B6 x DBA2 F1 hybrid mice
Transgenic APP levels in the brain were several-fold that
of endogenous mouse APP levels, Ab
levels dramatically and predictably increased most notably in the cerebral cortex
and hippocampus, increasing over 500-fold between 4 and 18 months of age.
Ab levels as well as
unidentified brain region-specific factors both appeared to be involved in amyloid
The transgenic mice at 3 month of age: significant hippocampal atrophy is observed.
The transgenic mice at 4-5 months of age: paired-pulse facilitation (PPF) is enhanced;
responses to high frequency stimulation bursts is distorted; long-term potentiation
(LTP) decays more rapidly.
In heterozygotic mice, between 4-6 months of age, no obvious pathology was
detected; however, at ~ 6-9 months of age, transgenic animals began to exhibit deposits
of human Ab in the
hippocampus, corpus callosum and cerebral cortex, but not in other brain regions.
These increased with age, and by 8 months, many deposits were seen. At age >9
months, the density of the plaques increased until the
Ab-staining pattern resembled that of AD.
By 18 months, they produce neuritic alterations and gliosis without widespread neuronal
Thioflavin S-positive Ab
deposits, neuritic plaques, synaptic loss, astrocytosis and microgliosis. No neurofibrillary
tangles or paired helical filaments have been found. There is a decrease in
the density of presynaptic terminals and neurons well before these mice develop
amyloid plaques. The development of structural and functional neuronal deficits
substantially preceds the formation of extracellular amyloid plaques.
Behavior and age of phenotype:
- Hyperactivity, 3, 6, 9 months; radial arm maze, 3 months (deficits appear before
amyloid plaque deposits); object recognition, 6, 9-10 months (decreases with time
may be associated with amyloid deposits); operant learning, 3, 6 months (Dodart
et al., 1999)
- WM spatial ref memory, 3-4, 10, 13, 18 months non-progressive; WM serial spatial
memory, 13, 18 months progressive (Chen et al., 2000)
- Cued fear cond, 11 months (Gerlai et al., 2002)
Sleep/wake patterns & holeboard spatial working memory, 3-5months, 20-26months progressive
(Huitron-Resendiz et al., 2002)
Not commercially available. Contact Dora Games or Dale Schenks at Elan Pharmaceutical.
Transgenic mouse expressing APP.sub.770
Wadsworth, Samuel; Snyder, Benjamin; Wei, Cha-Mer; Leibowitz, Paul J.
APP770 mutant in Alzheimer's disease
Imperial College of Science, Technology of Medicine/Hardy; John Anthony; Chartier-Harlin;
Marie-Christine ; Goate; Alison Mary ; Owen; Michael John; Mullan; Michael John
Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T,
Clemens J, Donaldson T, Gillespie F, et al. Alzheimer-type neuropathology in transgenic
mice overexpressing V717F beta-amyloid precursor protein. Nature 1995 Feb 9;373(6514):523-7
Rockenstein EM, McConlogue L, Tan H, Power M, Masliah E, Mucke L. Levels and alternative
splicing of amyloid beta protein precursor (APP) transcripts in brains of APP transgenic
mice and humans with Alzheimer's disease. J Biol Chem. 1995 Nov 24 ; 270(47):28257-67.
Gerlai R, Fitch T, Bales KR, Gitter BD. Behavioral impairment of APP (V717F) mice
in fear conditioning: is it only cognition? Behav Brain Res. 2002 Nov 15; 136(2):
Bacskai BJ, Kajdasz ST, McLellan ME, Games D, Seubert P, Schenk D, Hyman BT. Non-Fc-mediated
mechanisms are involved in clearance of amyloid-beta in vivo by immunotherapy. J
Neurosci. 2002 Sep 15;22(18):7873-8.
Huitron-Resendiz S, Sanchez-Alavez M, Gallegos R, Berg G, Crawford E, Giacchino
JL, Games D, Henriksen SJ, Criado JR. Age-independent and age-related deficits in
visuospatial learning, sleep-wake states, thermoregulation and motor activity in
PDAPP mice. Brain Res. 2002 Feb 22; 928(1-2): 126-37.
Bacskai BJ, Kajdasz ST, Christie RH, Carter C, Games D, Seubert P, Schenk D, Hyman
BT. Imaging of amyloid-beta deposits in brains of living mice permits direct observation
of clearance of plaques with immunotherapy. Nat Med. 2001 Mar ;7(3):369-72.
Chen G, Chen KS, Knox J, Inglis J, Bernard A, Martin SJ, Justice A, McConlogue L,
Games D, Freedman SB, Morris RG. A learning deficit related to age and beta-amyloid
plaques in a mouse model of Alzheimer's disease. Nature. 2000 Dec 21-28; 408(6815):
Bard F, Cannon C, Barbour R, Burke R-L, Games D, Grajeda H, Guido T, Hu K, Huang
J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M,
Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D and Yednock T. Peripherally
administered antibodies against amyloid b-peptide enter the central nervous system
and reduce pathology in a mouse model of Alzheimer disease. Nat Med.6:916-919, 2000.
Dodart JC, Meziane H, Mathis C, Bales KR, Paul SM, Ungerer A. Behavioral disturbances
in transgenic mice overexpressing the V717F beta-amyloid precursor protein. Behav
Neurosci. 1999 Oct; 113(5): 982-90.
Chen KS, Masliah E, Grajeda H, Guido T, Huang J, Khan K, Motter R, Soriano F, Games
D. Neurodegenerative Alzheimer-like pathology in PDAPP 717V-->F transgenic mice.
Prog Brain Res 1998;117:327-34
Dodart JC, Mathis C, Saura J, Bales KR, Paul SM, Ungerer A. Neuroanatomical abnormalities
in behaviorally characterized APP(V717F) transgenic mice. Neurobiol Dis 2000 Apr;7(2):71-85
Irizarry MC, Cheung BS, Rebeck GW, Paul SM, Bales KR, Hyman BT. Apolipoprotein E
affects the amount, form, and anatomical distribution of amyloid beta-peptide deposition
in homozygous APP(V717F) transgenic mice. Acta Neuropathol (Berl) 2000 Nov;100(5):451-8.
Irizarry MC, Soriano F, McNamara M, Page KJ, Schenk D, Games D, Hyman BT. Aβ
deposition is associated with neuropil changes, but not with overt neuronal loss
in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. J Neurosci
1997 Sep 15;17(18):7053-9
Larson J, Lynch G, Games D, Seubert P. Alterations in synaptic transmission and
long-term potentiation in hippocampal slices from young and aged PDAPP mice. Brain
Res 1999 Sep 4;840(1-2):23-35
Masliah E, Sisk A, Mallory M, Games D. Neurofibrillary pathology in transgenic mice
overexpressing V717F beta-amyloid precursor protein. J Neuropathol Exp Neurol 2001
Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood
K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano
F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert
P. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in
the PDAPP mouse. Nature 1999 Jul 8;400(6740):173-7