Journal of Literature Pharmacy Sciences

.: REVIEW
Alzheimer Hastalığı İn Vivo Modelleri: Geleneksel Derleme
Alzheimer's Disease In Vivo Models: A Traditional Review
Sena TÜTÜNCÜa, Hülya TEZELb, Aylin BALCI ÖZYURTb, Anıl YİRÜNb, Terken BAYDARb, Pınar ERKEKOĞLUb
aTOBB Ekonomi ve Teknoloji Üniversitesi Mühendislik Fakültesi, Biyomedikal Mühendisliği, Ankara, Türkiye
bHacettepe Üniversitesi Eczacılık Fakültesi, Farmasötik Toksikoloji ABD, Ankara, Türkiye
J Lit Pharm Sci. 2023;12(1):8-19
doi: 10.5336/pharmsci.2022-90431
Article Language: TR
Full Text
ÖZET
Nörodejeneratif hastalıklardan biri olan Alzheimer hastalığı (AH), günümüzde yaygın olarak görülen ve hafıza kaybı, bilişsel işlevlerde bozulma ve ilerleyen zamanlarda günlük aktiviteleri yerine getirememeyle kendini gösteren bir demans türüdür. Sadece palyatif tedavisi olan bu hastalıkta, beyinde kademeli olarak artan ve geri dönüşümü olmayan bir hasar meydana gelmektedir. Bu hastalığın etiyolojini araştırmak için son yıllarda çok sayıda in vitro ve in vivo model geliştirilmektedir. Araştırmacılar, hayvan modelleri ile AH'nin lezyonlarını, semptomlarını veya nedenlerini taklit etmeye çalışmaktadır. AH üzerine yapılan araştırmalarda, hayvan kullanmanın çeşitli avantajları bulunmaktadır. AH hayvan modelleri geliştirilirken, hastalıkta 'amiloid plak' ve 'nörofibriler yumakların' birikimi olduğu için 'βamiloid' ve 'Tau proteini' modelleri üzerine odaklanılmıştır. Bu farklı modeller, araştırıcıların manipülasyon yeteneklerini artırabilmektedir. Ayrıca deney hayvanlarının yaşam süresi kısa olduğu için modeli oluşturmak ve sonuçlarını görmek hızlı bir şekilde gerçekleşebilmektedir ve kararlı laboratuvar koşulları, çevresel ve fizyolojik etmenlerin etkisini azaltmaktadır. Hayvanlardaki fizyolojik değişiklikler de daha yakından izlenebilmektedir. Ancak bu modeller, AH'nin temel özelliklerini ortaya çıkarsa da hiçbiri insan beyninde gözlenen patolojik özellikleri tam olarak taklit etmemektedir. Geliştirilen AH modelleri, genel olarak 'transgenik' ve 'transgenik olmayan' hayvanlar üzerinde yapılmaktadır. Transgenik hayvan modeli olarak, çalışmaların büyük bir kısmında fareler kullanılmaktadır. Bu geleneksel derlemede, AH araştırmalarında kullanılan in vivo modelleri olan Tg2576, APP23, PDAPP, PSEN1, JNPL3 ve TAPP fare modelleri hakkında güncel bilgiler özetlenmiş ve bu modellerin üstünlükleri ve dezavantajları tartışılmıştır.

Anahtar Kelimeler: Alzheimer hastalığı; hayvan modelleri; Tau; amiloid beta; nörofibriler yumak
ABSTRACT
Alzheimer's disease (AD), a neurodegenerative disease, is a common dementia that presents itself with memory loss, deterioration in cognitive functions and inability to perform daily activities in the future. In this disease, which has only palliative treatment, gradual increase and irreversible damage in the brain occurs. Numerous in vitro and in vivo models have been developed in recent years to investigate the etiology of the disease. Researchers are trying to mimic the lesions, symptoms or causes of AD with animal models. There are several advantages of using animals in research on AD. Animal models of AD have focused on 'β-amyloid' and 'Tau protein' models because of the accumulation of 'amyloid plaque' and 'neurofibrillary tangles' in the disease. These different models can increase manipulation abilities of researchers. In addition, since life span of experimental animals is short, creating the model and seeing the results can be faster and under stable laboratory conditions, effects of environmental and physiological factors can be reduced. Physiological changes in animals can also be monitored more closely. However, although these models reveal basic features of AD, none of them fully mimic the pathological features observed in the human brain. Developed AD models are generally performed on 'transgenic' and 'nontransgenic' animals. Mice are used in the majority of transgenic animal models. In this traditional review, up-to-date information about Tg2576, APP23, PDAPP, PSEN1, JNPL3 and TAPP mouse models, which are in vivo models used in AD research, are compiled and advantages and disadvantages of these models are discussed.

Keywords: Alzheimer's disease; animal models; Tau; amyloid beta; neurofibrillary tangle
REFERENCES:
  1. Alzheimer's Association Report. Alzheimer's disease facts and figures. Alzheimer's & Dementia. 2017;13(4):325-73. [Crossref] 
  2. World Health Organization. Global action plan on the public health response to dementia 2017-2025. Cited: April 06, 2022. Available from: [Link] 
  3. Carter CL, Resnick EM, Mallampalli M, Kalbarczyk A. Sex and gender differences in Alzheimer's disease: recommendations for future research. J Womens Health (Larchmt). 2012;21(10):1018-23. [Crossref]  [PubMed] 
  4. Jankowsky JL, Zheng H. Practical considerations for choosing a mouse model of Alzheimer's disease. Mol Neurodegener. 2017;12(1):89. [Crossref]  [PubMed]  [PMC] 
  5. Puzzo D, Gulisano W, Palmeri A, Arancio O. Rodent models for Alzheimer's disease drug discovery. Expert Opin Drug Discov. 2015;10(7):703-11. [Crossref]  [PubMed]  [PMC] 
  6. Faber-Langendoen K, Morris JC, Knesevich JW, LaBarge E, Miller JP, Berg L. Aphasia in senile dementia of the Alzheimer type. Ann Neurol. 1988;23(4):365-70. [Crossref]  [PubMed] 
  7. Wirths O, Weis J, Szczygielski J, Multhaup G, Bayer TA. Axonopathy in an APP/PS1 transgenic mouse model of Alzheimer's disease. Acta Neuropathol. 2006;111(4):312-9. [Crossref]  [PubMed] 
  8. Chabrier MA, Neely KM, Castello NA, Frank M. The Contribution of Transgenic Models to the Understanding of Alzheimer's Disease Progression and Therapeutic Development. Avila J, Lucas JJ, Hernández F, eds. Animal Models for Neurodegenerative Disease. 1st ed. Cambridge, UK: Royal Society Chemistry; 2011. p.1-14. [Crossref] 
  9. Blessed G, Tomlinson BE, Roth M. The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. Br J Psychiatry. 1968;114(512):797-811. [Crossref]  [PubMed] 
  10. Braak H, Braak E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging. 1997;18(4):351-7. [Crossref]  [PubMed] 
  11. Yamaguchi H, Hirai S, Morimatsu M, Shoji M, Ihara Y. A variety of cerebral amyloid deposits in the brains of the Alzheimer-type dementia demonstrated by beta protein immunostaining. Acta Neuropathol. 1988;76(6):541-9. [Crossref]  [PubMed] 
  12. Bird TD. Genetic factors in Alzheimer disease and dementia. In: Speicher MR, Motulsky AG, Antonarakis SE, eds. Vogel and Motulsky's Human Genetics. 4th ed. Berlin, Heidelberg: Springer; 2010. p.681-97.
  13. Götz J, Götz NN. Animal models for Alzheimer's disease and frontotemporal dementia: a perspective. ASN Neuro. 2009;1(4):e00019. [Crossref]  [PubMed]  [PMC] 
  14. Dorszewska J, Prendecki M, Oczkowska A, Dezor M, Kozubski W. Molecular basis of familial and sporadic Alzheimer's disease. Curr Alzheimer Res. 2016;13(9):952-63. [Crossref]  [PubMed] 
  15. Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, et al. Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature. 1996;383(6602):710-3. [Crossref]  [PubMed] 
  16. Hardy J. The amyloid hypothesis for Alzheimer's disease: a critical reappraisal. J Neurochem. 2009;110(4):1129-34. [Crossref]  [PubMed] 
  17. LaFerla FM, Green KN. Animal models of Alzheimer disease. Cold Spring Harb Perspect Med. 2012;2(11):a006320. [Crossref]  [PubMed]  [PMC] 
  18. Mori C, Spooner ET, Wisniewsk KE, Wisniewski TM, Yamaguch H, Saido TC, et al. Intraneuronal Abeta42 accumulation in Down syndrome brain. Amyloid. 2002;9(2):88-102. [Crossref]  [PubMed] 
  19. Burbach GJ, Hellweg R, Haas CA, Del Turco D, Deicke U, Abramowski D, et al. Induction of brain-derived neurotrophic factor in plaque-associated glial cells of aged APP23 transgenic mice. J Neurosci. 2004;24(10):2421-30. [Crossref]  [PubMed]  [PMC] 
  20. Bilkei-Gorzo A. Genetic mouse models of brain ageing and Alzheimer's disease. Pharmacol Ther. 2014;142(2):244-57. [Crossref]  [PubMed] 
  21. Hsia AY, Masliah E, McConlogue L, Yu GQ, Tatsuno G, Hu K, et al. Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. Proc Natl Acad Sci U S A. 1999;96(6):3228-33. [Crossref]  [PubMed]  [PMC] 
  22. Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, et al. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci. 2000;20(11):4050-8. [Crossref]  [PubMed]  [PMC] 
  23. Selkoe DJ. Toward a comprehensive theory for Alzheimer's disease. Hypothesis: Alzheimer's disease is caused by the cerebral accumulation and cytotoxicity of amyloid beta-protein. Ann N Y Acad Sci. 2000;924:17-25. [Crossref]  [PubMed] 
  24. Galvan V, Gorostiza OF, Banwait S, Ataie M, Logvinova AV, Sitaraman S, et al. Reversal of Alzheimer's-like pathology and behavior in human APP transgenic mice by mutation of Asp664. Proc Natl Acad Sci U S A. 2006;103(18):7130-5. Erratum in: Proc Natl Acad Sci U S A. 2007;104(16):6876. [Crossref]  [PubMed]  [PMC] 
  25. Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, et al. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron. 2007;55(5):697-711. [Crossref]  [PubMed]  [PMC] 
  26. Beauquis J, Pavía P, Pomilio C, Vinuesa A, Podlutskaya N, Galvan V, et al. Environmental enrichment prevents astroglial pathological changes in the hippocampus of APP transgenic mice, model of Alzheimer's disease. Exp Neurol. 2013;239:28-37. [Crossref]  [PubMed] 
  27. Haughey NJ, Nath A, Chan SL, Borchard AC, Rao MS, Mattson MP. Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer's disease. J Neurochem. 2002;83(6):1509-24. [Crossref]  [PubMed] 
  28. Sarasa M, Pesini P. Natural non-trasgenic animal models for research in Alzheimer's disease. Curr Alzheimer Res. 2009;6(2):171-8. [Crossref]  [PubMed]  [PMC] 
  29. Axelman K, Basun H, Winblad B, Lannfelt L. A large Swedish family with Alzheimer's disease with a codon 670/671 amyloid precursor protein mutation. A clinical and genealogical investigation. Arch Neurol. 1994;51(12):1193-7. [Crossref]  [PubMed] 
  30. Esquerda-Canals G, Montoliu-Gaya L, Güell-Bosch J, Villegas S. Mouse models of Alzheimer's disease. J Alzheimers Dis. 2017;57(4):1171-83. [Crossref]  [PubMed] 
  31. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science. 1996;274(5284):99-102. [Crossref]  [PubMed] 
  32. George AJ, Holsinger RM, McLean CA, Laughton KM, Beyreuther K, Evin G, et al. APP intracellular domain is increased and soluble Abeta is reduced with diet-induced hypercholesterolemia in a transgenic mouse model of Alzheimer disease. Neurobiol Dis. 2004;16(1):124-32. [Crossref]  [PubMed] 
  33. Barrett JE, McGonigle P. Rodent Models for Alzheimer's Disease in Drug Discovery. Drug Discovery Approaches for the Treatment of Neurodegenerative Disorders. 2017;235-47. [Crossref]  [PubMed]  [PMC] 
  34. Stein TD, Johnson JA. Lack of neurodegeneration in transgenic mice overexpressing mutant amyloid precursor protein is associated with increased levels of transthyretin and the activation of cell survival pathways. J Neurosci. 2002;22(17):7380-8. [Crossref]  [PubMed]  [PMC] 
  35. AbdAlla S, Langer A, Fu X, Quitterer U. ACE inhibition with captopril retards the development of signs of neurodegeneration in an animal model of Alzheimer's disease. Int J Mol Sci. 2013;14(8):16917-42. [Crossref]  [PubMed]  [PMC] 
  36. Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci U S A. 1997;94(24):13287-92. [Crossref]  [PubMed]  [PMC] 
  37. Higuchi M. Visualization of brain amyloid and microglial activation in mouse models of Alzheimer's disease. Curr Alzheimer Res. 2009;6(2):137-43. [Crossref]  [PubMed] 
  38. Heneka MT, Ramanathan M, Jacobs AH, Dumitrescu-Ozimek L, Bilkei-Gorzo A, Debeir T, et al. Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. J Neurosci. 2006;26(5):1343-54. [Crossref]  [PubMed]  [PMC] 
  39. Beckmann N, Schuler A, Mueggler T, Meyer EP, Wiederhold KH, Staufenbiel M, et al. Age-dependent cerebrovascular abnormalities and blood flow disturbances in APP23 mice modeling Alzheimer's disease. J Neurosci. 2003;23(24):8453-9. [Crossref]  [PubMed]  [PMC] 
  40. Choi JH, Kaur G, Mazzella MJ, Morales-Corraliza J, Levy E, Mathews PM. Early endosomal abnormalities and cholinergic neuron degeneration in amyloid-β protein precursor transgenic mice. J Alzheimers Dis. 2013;34(3):691-700. [Crossref]  [PubMed]  [PMC] 
  41. Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature. 1995;373(6514):523-7. [Crossref]  [PubMed] 
  42. Irizarry MC, McNamara M, Fedorchak K, Hsiao K, Hyman BT. APPSw transgenic mice develop age-related A beta deposits and neuropil abnormalities, but no neuronal loss in CA1. J Neuropathol Exp Neurol. 1997;56(9):965-73. [Crossref]  [PubMed] 
  43. Su Y, Ni B. Selective deposition of amyloid-beta protein in the entorhinal-dentate projection of a transgenic mouse model of Alzheimer's disease. J Neurosci Res. 1998;53(2):177-86. [Crossref]  [PubMed] 
  44. 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;113(5):982-90. [Crossref]  [PubMed] 
  45. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999;400(6740):173-7. [Crossref]  [PubMed] 
  46. German DC, Yazdani U, Speciale SG, Pasbakhsh P, Games D, Liang CL. Cholinergic neuropathology in a mouse model of Alzheimer's disease. J Comp Neurol. 2003;462(4):371-81. [Crossref]  [PubMed] 
  47. Weiner HL, Lemere CA, Maron R, Spooner ET, Grenfell TJ, Mori C, et al. Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease. Ann Neurol. 2000;48(4):567-79. [Crossref]  [PubMed] 
  48. DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2001;98(15):8850-5. [Crossref]  [PubMed]  [PMC] 
  49. Donovan MH, Yazdani U, Norris RD, Games D, German DC, Eisch AJ. Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer's disease. J Comp Neurol. 2006;495(1):70-83. [Crossref]  [PubMed] 
  50. Bales KR, Verina T, Dodel RC, Du Y, Altstiel L, Bender M, et al. Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat Genet. 1997;17(3):263-4. [Crossref]  [PubMed] 
  51. Selwood SP, Parvathy S, Cordell B, Ryan HS, Oshidari F, Vincent V, et al. Gene expression profile of the PDAPP mouse model for Alzheimer's disease with and without Apolipoprotein E. Neurobiol Aging. 2009;30(4):574-90. [Crossref]  [PubMed] 
  52. Oksanen M, Petersen AJ, Naumenko N, Puttonen K, Lehtonen ?, Gubert Olivé M, et al. PSEN1 Mutant iPSC-derived model reveals severe astrocyte pathology in Alzheimer's disease. Stem Cell Reports. 2017;9(6):1885-97. [Crossref]  [PubMed]  [PMC] 
  53. Liao MC, Muratore CR, Gierahn TM, Sullivan SE, Srikanth P, De Jager PL, et al. Single-cell detection of secreted Aβ and sAPPα from human IPSC-derived neurons and astrocytes. J Neurosci. 2016;36(5):1730-46. [Crossref]  [PubMed]  [PMC] 
  54. Hoffman JL, Faccidomo S, Kim M, Taylor SM, Agoglia AE, May AM, et al. Alcohol drinking exacerbates neural and behavioral pathology in the 3xTg-AD mouse model of Alzheimer's disease. Int Rev Neurobiol. 2019;148:169-230. [Crossref]  [PubMed]  [PMC] 
  55. Kim HJ, Kim DJ, Shin EJ, Lee BH, Choi SH, Hwang SH, et al. Effects of gintonin-enriched fraction on hippocampal cell proliferation in wild-type mice and an APPswe/PSEN-1 double Tg mouse model of Alzheimer's disease. Neurochem Int. 2016;101:56-65. [Crossref]  [PubMed] 
  56. Elçioğlu HK, Yılmaz G, İlhan B, Karan MA. Alzheimer hastalığında deneysel hayvan modelleri [Experimental animal models for Alzheimer disease]. Nobel Med. 2018;14(1):5-13. [Link] 
  57. Leon WC, Canneva F, Partridge V, Allard S, Ferretti MT, DeWilde A, et al. A novel transgenic rat model with a full Alzheimer's-like amyloid pathology displays pre-plaque intracellular amyloid-beta-associated cognitive impairment. J Alzheimers Dis. 2010;20(1):113-26. [Crossref]  [PubMed] 
  58. Nilsen LH, Melø TM, Saether O, Witter MP, Sonnewald U. Altered neurochemical profile in the McGill-R-Thy1-APP rat model of Alzheimer's disease: a longitudinal in vivo 1 H MRS study. J Neurochem. 2012;123(4):532-41. [Crossref]  [PubMed] 
  59. Wilson EN, Do Carmo S, Welikovitch LA, Hall H, Aguilar LF, Foret MK, et al. NP03, a microdose lithium formulation, blunts early amyloid post-plaque neuropathology in McGill-R-Thy1-APP Alzheimer-like transgenic rats. J Alzheimers Dis. 2020;73(2):723-39. [Crossref]  [PubMed] 
  60. Lewis J, McGowan E, Rockwood J, Melrose H, Nacharaju P, Van Slegtenhorst M, et al. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet. 2000;25(4):402-5. [Crossref]  [PubMed] 
  61. Vega IE, Umstead A, Wygant CM, Beck JS, Counts SE. Ezrin expression is increased during disease progression in a tauopathy mouse model and Alzheimer's disease. Curr Alzheimer Res. 2018;15(12):1086-95. [Crossref]  [PubMed]  [PMC] 
  62. Krishnamurthy PK, Deng Y, Sigurdsson EM. Mechanistic studies of antibody-mediated clearance of tau aggregates using an ex vivo brain slice model. Front Psychiatry. 2011;2:59. [Crossref]  [PubMed]  [PMC] 
  63. Fukuhara K, Ohno A, Ota Y, Senoo Y, Maekawa K, Okuda H, et al. NMR-based metabolomics of urine in a mouse model of Alzheimer's disease: identification of oxidative stress biomarkers. J Clin Biochem Nutr. 2013;52(2):133-8. [Crossref]  [PubMed]  [PMC] 
  64. Marquez A, Guernsey LS, Frizzi KE, Cundiff M, Constantino I, Muttalib N, et al. Tau associated peripheral and central neurodegeneration: identification of an early imaging marker for tauopathy. Neurobiol Dis. 2021;151:105273. [Crossref]  [PubMed]  [PMC] 
  65. Schaeffer EL, Figueiro M, Gattaz WF. Insights into Alzheimer disease pathogenesis from studies in transgenic animal models. Clinics (Sao Paulo). 2011;66 Suppl 1(Suppl 1):45-54. [Crossref]  [PubMed]  [PMC] 
  66. Arendash GW, Lewis J, Leighty RE, McGowan E, Cracchiolo JR, Hutton M, et al. Multi-metric behavioral comparison of APPsw and P301L models for Alzheimer's disease: linkage of poorer cognitive performance to tau pathology in forebrain. Brain Res. 2004;1012(1-2):29-41. [Crossref]  [PubMed] 
  67. Saydoff JA, Olariu A, Sheng J, Hu Z, Li Q, Garcia R, et al. Uridine prodrug improves memory in Tg2576 and TAPP mice and reduces pathological factors associated with Alzheimer's disease in related models. J Alzheimers Dis. 2013;36(4):637-57. [Crossref]  [PubMed] 
  68. Heuer E, Rosen RF, Cintron A, Walker LC. Nonhuman primate models of Alzheimer-like cerebral proteopathy. Curr Pharm Des. 2012;18(8):1159-69. [Crossref]  [PubMed]  [PMC] 
  69. Toledano A, Alvarez MI, López-Rodríguez AB, Toledano-Díaz A, Fernández-Verdecia CI. [Does Alzheimer's disease exist in all primates? Alzheimer pathology in non-human primates and its pathophysiological implications (I)]. Neurologia. 2012;27(6):354-69. [Crossref]  [PubMed] 
  70. Duyckaerts C, Potier MC, Delatour B. Alzheimer disease models and human neuropathology: similarities and differences. Acta Neuropathol. 2008;115(1):5-38. [Crossref]  [PubMed]  [PMC] 
  71. Cavanaugh SE, Pippin JJ, Barnard ND. Animal models of Alzheimer disease: historical pitfalls and a path forward. ALTEX. 2014;31(3):279-302. [Crossref]  [PubMed] 
  72. Ashe KH. Mechanisms of memory loss in Abeta and tau mouse models. Biochem Soc Trans. 2005;33(Pt 4):591-4. [Crossref]  [PubMed] 
  73. Dodart JC, Mathis C, Ungerer A. The beta-amyloid precursor protein and its derivatives: from biology to learning and memory processes. Rev Neurosci. 2000;11(2-3):75-93. [Crossref]  [PubMed] 
  74. Kuo YM, Kokjohn TA, Beach TG, Sue LI, Brune D, Lopez JC, et al. Comparative analysis of amyloid-beta chemical structure and amyloid plaque morphology of transgenic mouse and Alzheimer's disease brains. J Biol Chem. 2001;276(16):12991-8. [Crossref]  [PubMed] 
  75. Schwab C, Hosokawa M, McGeer PL. Transgenic mice overexpressing amyloid beta protein are an incomplete model of Alzheimer disease. Exp Neurol. 2004;188(1):52-64. [Crossref]  [PubMed] 

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- Providing structural, statistical and editorial support to article preparation stage for scientific journals.

4. GENERAL PROVISIONS

4.1. "Turkiye Klinikleri" is completely free to determine which of the services and contents provided in the "SITE" will be charged.

4.2. People benefiting from the services provided by "Turkiye Klinikleri" and using the website can use the "SITE" only according to the law and only for personal reasons. Users have the criminal and civil liability for every process and action they take in the "SITE". Every USER agrees, declares and undertakes that they will not proceed by any function or action infringement of rights of "Turkiye Klinikleri"s and/or other third parties', they are the exclusive right holder on usage, processing, storage, made public and revealing any written, visual or auditory information reported to Turkiye Klinikleri" and/or "SITE" to the third parties. "USER" agrees and undertakes that s/he will not duplicate, copy, distribute, process, the pictures, text, visual and auditory images, video clips, files, databases, catalogs and lists within the "SITE", s/he will not be using these actions or with other ways to compete with "Turkiye Klinikleri", directly or indirectly.

4.3. The services provided and the context published within the "SITE" by third parties is not under the responsibility of "Turkiye Klinikleri", institutions collaborated with "Turkiye Klinikleri", "Turkiye Klinikleri" employee and directors, "Turkiye Klinikleri" authorized salespeople. Commitment to accuracy and legality of the published information, context, visual and auditory images provided by any third party are under the full responsibility of the third party. "Turkiye Klinikleri" does not promise and guarantee the safety, accuracy and legality of the services and context provided by a third party.

4.4. "USER"s cannot act against "Turkiye Klinikleri", other "USER"s and third parties by using the "SITE". "Turkiye Klinikleri" has no direct and/or indirect responsibility for any damage a third party suffered or will suffer regarding "USER"s actions on the "SITE" against the rules of the hereby "Terms of Use" and the law.

4.5. "USER"s accept and undertake that the information and context they provided to the "SITE" are accurate and legal. "Turkiye Klinikleri" is not liable and responsible for promising and guaranteeing the verification of the information and context transmitted to "Turkiye Klinikleri" by the "USER"s, or uploaded, changed and provided through the "SITE" by them and whether these information are safe, accurate and legal.

4.6. "USER"s agree and undertake that they will not perform any action leading to unfair competition, weakening the personal and commercial credit of "Turkiye Klinikleri" and a third party,  encroaching and attacking on personal rights within the "SITE" in accordance with the Turkish Commercial Code Law.

4.7. "Turkiye Klinikleri" reserves the right to change the services and the context within the "SITE"  anytime. "Turkiye Klinikleri" may use this right without any notification and timelessly. "USER"s have to make the changes and/or corrections "Turkiye Klinikleri" required immediately. Any changes and/or corrections that are required by "Turkiye Klinikleri", may be made by "Turkiye Klinikleri" when needed. Any harm, criminal and civil liability resulted or will result from changes and/or corrections required by "Turkiye Klinikleri" and were not made on time by the "USER"s belongs completely to the users.

4.8. "Turkiye Klinikleri" may give links through the "SITE" to other websites and/or "CONTEXT"s and/or folders that are outside of their control and owned and run by third parties. These links are provided for ease of reference only and do not hold qualification for support the respective web SITE or the admin or declaration or guarantee for the information inside. "Turkiye Klinikleri" does not hold any responsibility over the web-sites connected through the links on the "SITE", folders and context, the services or products on the websites provided through these links or their context.

4.9. "Turkiye Klinikleri" may use the information provided to them by the "USERS" through the "SITE" in line with the terms of the "PRIVACY POLICY" and "USER CONTRACT". It may process the information or classify and save them on a database. "Turkiye Klinikleri" may also use the USER's or visitor's identity, address, e-mail address, phone number, IP number, which sections of the "SITE" they visited, domain type, browser type, date and time information to provide statistical evaluation and customized services.

5. PROPRIETARY RIGHTS

5.1. The information accessed through this "SITE" or provided by the users legally and all the elements (including but not limited to design, text, image, html code and other codes) of the "SITE" (all of them will be called as studies tied to "Turkiye Klinikleri"s copyrights) belongs to "Turkiye Klinikleri". Users do not have the right to resell, process, share, distribute, display or give someone permission to access or to use the "Turkiye Klinikleri" services, "Turkiye Klinikleri" information and the products under copyright protection by "Turkiye Klinikleri". Within hereby "Terms of Use" unless explicitly permitted by "Turkiye Klinikleri" nobody can reproduce, process, distribute or produce or prepare any study from those under "Turkiye Klinikleri" copyright protection.

5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com