Updated 30 October 2005

General Information

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

Phenotype

Neuropathological analysis:

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 plaque deposition.

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 death.

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)

Availability

Not commercially available.  Contact Dora Games or Dale Schenks at Elan Pharmaceutical.

Patents:

Reference

Primary:

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 Abstract

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. Abstract

Secondary:

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): 503-9. Abstract

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. Abstract

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. Abstract

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. Abstract

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): 975-9. Abstract

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. Abstract

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. Abstract

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 Abstract

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 Abstract

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. Abstract.

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 Abstract

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 Abstract

Masliah E, Sisk A, Mallory M, Games D. Neurofibrillary pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. J Neuropathol Exp Neurol 2001 Apr;60(4):357-68. Abstract.

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 Abstract