A canine model of Alzheimer's disease generated by overexpressing a mutated human amyloid precursor protein

Lee,Geun-Shik; Jeong,Yeon Woo; Kim,Joung Joo; Park,Sun Woo; Ko,Kyeong Hee; Kang,Mina; Kim,Yu Kyung; Jung,Eui-Man; Moon,Changjong; Hyun,Sang Hwan; Hwang,Kyu‑Chan; Kim,Nam-Hyung; Shin,Taeyoung; Jeung,Eui-Bae; Hwang,Woo Suk

doi:10.3892/ijmm.2014.1636

A canine model of Alzheimer's disease generated by overexpressing a mutated human amyloid precursor protein

Authors:
- Geun-Shik Lee
- Yeon Woo Jeong
- Joung Joo Kim
- Sun Woo Park
- Kyeong Hee Ko
- Mina Kang
- Yu Kyung Kim
- Eui-Man Jung
- Changjong Moon
- Sang Hwan Hyun
- Kyu‑Chan Hwang
- Nam-Hyung Kim
- Taeyoung Shin
- Eui-Bae Jeung
- Woo Suk Hwang
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Affiliations: College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chucheon, Gangwon 200‑701, Republic of Korea, SooAm Biotech Research Foundation, Seoul 152-904, Republic of Korea, Laboratory of Veterinary Biochemistry and Molecular Biology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 361-763, Republic of Korea, Department of Veterinary Anatomy, College of Veterinary Medical Institute, Chonnam National University, Gwangju, Gyeonggi 500-757, Republic of Korea, Laboratory of Veterinary Embryology and Biotechnology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 361-763, Republic of Korea, Department of Animal Science, Chungbuk National University, Cheongju, Chungbuk 361-763, Republic of Korea
Published online on: January 28, 2014 https://doi.org/10.3892/ijmm.2014.1636
Pages: 1003-1012

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Abstract

Canines are considered the most authentic model for studying multifactorial human diseases, as these animals typically share a common environment with man. Somatic cell nuclear transfer (SCNT) technology along with genetic engineering of nuclear donor cells provides a unique opportunity for examining human diseases using transgenic canines. In the present study, we generated transgenic canines that overexpressed the human amyloid precursor protein (APP) gene containing well-characterized familial Alzheimer's disease (AD) mutations. We successfully obtained five out of six live puppies by SCNT. This was confirmed by observing the expression of green fluorescence protein in the body as a visual transgenic marker and the overexpression of the mutated APP gene in the brain. The transgenic canines developed AD-like symptoms, such as enlarged ventricles, an atrophied hippocampus, and β-amyloid plaques in the brain. Thus, the transgenic canines we created can serve as a novel animal model for studying human AD.

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1	Rocchi A, Pellegrini S, Siciliano G and Murri L: Causative and susceptibility genes for Alzheimer’s disease: a review. Brain Res Bull. 61:1–24. 2003.
2	Götz J, Streffer JR, David D, et al: Transgenic animal models of Alzheimer’s disease and related disorders: histopathology, behavior and therapy. Mol Psychiatry. 9:664–683. 2004.
3	Head E, Pop V, Sarsoza F, et al: Amyloid-beta peptide and oligomers in the brain and cerebrospinal fluid of aged canines. J Alzheimers Dis. 20:637–646. 2010.PubMed/NCBI
4	Kragh PM, Nielsen AL, Li J, et al: Hemizygous minipigs produced by random gene insertion and handmade cloning express the Alzheimer’s disease-causing dominant mutation APPsw. Transgenic Res. 18:545–558. 2009.PubMed/NCBI
5	Jang G, Kim MK, Oh HJ, et al: Birth of viable female dogs produced by somatic cell nuclear transfer. Theriogenology. 67:941–947. 2007. View Article : Google Scholar : PubMed/NCBI
6	Duyckaerts C, Potier MC and Delatour B: Alzheimer disease models and human neuropathology: similarities and differences. Acta Neuropathol. 115:5–38. 2008. View Article : Google Scholar : PubMed/NCBI
7	Hong SG, Kim MK, Jang G, et al: Generation of red fluorescent protein transgenic dogs. Genesis. 47:314–322. 2009. View Article : Google Scholar : PubMed/NCBI
8	Hossein MS, Kim MK, Jang G, et al: Effects of thiol compounds on in vitro maturation of canine oocytes collected from different reproductive stages. Mol Reprod Dev. 74:1213–1220. 2007. View Article : Google Scholar : PubMed/NCBI
9	Lee BC, Kim MK, Jang G, et al: Dogs cloned from adult somatic cells. Nature. 436:6412005. View Article : Google Scholar : PubMed/NCBI
10	Spanopoulou E, Giguere V and Grosveld F: The functional domains of the murine Thy-1 gene promoter. Mol Cell Biol. 11:2216–2228. 1991.PubMed/NCBI
11	Dudal S, Krzywkowski P, Paquette J, et al: Inflammation occurs early during the Abeta deposition process in TgCRND8 mice. Neurobiol Aging. 25:861–871. 2004. View Article : Google Scholar : PubMed/NCBI
12	Spires TL and Hyman BT: Transgenic models of Alzheimer’s disease: learning from animals. NeuroRx. 2:423–437. 2005.
13	Friedman D, Honig LS and Scarmeas N: Seizures and epilepsy in Alzheimer’s disease. CNS Neurosci Ther. 18:285–294. 2012.
14	Irizarry MC, Jin S, He F, et al: Incidence of new-onset seizures in mild to moderate Alzheimer disease. Arch Neurol. 69:368–372. 2012. View Article : Google Scholar : PubMed/NCBI
15	Larner AJ and Marson AG: Epileptic seizures in Alzheimer’s disease: another fine MESS? J Alzheimers Dis. 25:417–419. 2011.
16	Pandis D and Scarmeas N: Seizures in Alzheimer disease: clinical and epidemiological data. Epilepsy Curr. 12:184–187. 2012. View Article : Google Scholar : PubMed/NCBI
17	Picco A, Archetti S, Ferrara M, et al: Seizures can precede cognitive symptoms in late-onset Alzheimer’s disease. J Alzheimers Dis. 27:737–742. 2011.PubMed/NCBI
18	Apostolova LG, Green AE, Babakchanian S, et al: Hippocampal atrophy and ventricular enlargement in normal aging, mild cognitive impairment (MCI), and Alzheimer Disease. Alzheimer Dis Assoc Disord. 26:17–27. 2012. View Article : Google Scholar : PubMed/NCBI
19	Chou YY, Leporé N, Avedissian C, et al: Mapping correlations between ventricular expansion and CSF amyloid and tau biomarkers in 240 subjects with Alzheimer’s disease, mild cognitive impairment and elderly controls. Neuroimage. 46:394–410. 2009.PubMed/NCBI
20	Ferrarini L, Palm WM, Olofsen H, et al: MMSE scores correlate with local ventricular enlargement in the spectrum from cognitively normal to Alzheimer disease. Neuroimage. 39:1832–1838. 2008. View Article : Google Scholar : PubMed/NCBI
21	Nestor SM, Rupsingh R, Borrie M, et al: Ventricular enlargement as a possible measure of Alzheimer’s disease progression validated using the Alzheimer’s disease neuroimaging initiative database. Brain. 131:2443–2454. 2008.PubMed/NCBI
22	Glass CK, Saijo K, Winner B, Marchetto MC and Gage FH: Mechanisms underlying inflammation in neurodegeneration. Cell. 140:918–934. 2010. View Article : Google Scholar : PubMed/NCBI
23	Dyrks T, Weidemann A, Multhaup G, et al: Identification, transmembrane orientation and biogenesis of the amyloid A4 precursor of Alzheimer’s disease. EMBO J. 7:949–957. 1988.PubMed/NCBI
24	Selkoe DJ: Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev. 81:741–766. 2001.
25	Sisodia SS: Beta-amyloid precursor protein cleavage by a membrane-bound protease. Proc Natl Acad Sci USA. 89:6075–6079. 1992. View Article : Google Scholar : PubMed/NCBI
26	Sarasa M and Pesini P: Natural non-trasgenic animal models for research in Alzheimer’s disease. Curr Alzheimer Res. 6:171–178. 2009.PubMed/NCBI
27	Head E: Combining an antioxidant-fortified diet with behavioral enrichment leads to cognitive improvement and reduced brain pathology in aging canines: strategies for healthy aging. Ann NY Acad Sci. 1114:398–406. 2007. View Article : Google Scholar : PubMed/NCBI
28	Siwak-Tapp CT, Head E, Muggenburg BA, Milgram NW and Cotman CW: Region specific neuron loss in the aged canine hippocampus is reduced by enrichment. Neurobiol Aging. 29:39–50. 2008. View Article : Google Scholar : PubMed/NCBI
29	Head E, Mehta R, Hartley J, et al: Spatial learning and memory as a function of age in the dog. Behav Neurosci. 109:851–858. 1995. View Article : Google Scholar : PubMed/NCBI
30	Adams B, Chan A, Callahan H, et al: Use of a delayed non-matching to position task to model age-dependent cognitive decline in the dog. Behav Brain Res. 108:47–56. 2000. View Article : Google Scholar : PubMed/NCBI
31	Smith DR, Hoyt EC, Gallagher M, Schwabe RF and Lund PK: Effect of age and cognitive status on basal level AP-1 activity in rat hippocampus. Neurobiol Aging. 22:773–786. 2001. View Article : Google Scholar : PubMed/NCBI
32	Sokol DL and Gewirtz AM: Gene therapy: basic concepts and recent advances. Crit Rev Eukaryot Gene Expr. 6:29–57. 1996. View Article : Google Scholar : PubMed/NCBI
33	Martin SB, Dowling AL and Head E: Therapeutic interventions targeting Beta amyloid pathogenesis in an aging dog model. Curr Neuropharmacol. 9:651–661. 2011. View Article : Google Scholar : PubMed/NCBI