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Psychiatric Disorders pp 393–412Cite as

An Animal Model to Test Reversal of Cognitive Decline Associated with Beta-Amyloid Pathologies

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Part of the book series: Methods in Molecular Biology ((MIMB,volume 2011))

Abstract

Disposition of beta-amyloid peptide 1–42 (Aβ1–42) in the space around the synapses and formation of Aβ-containing aggregates known as neuritic or senile plaques are hallmark features of neurodegenerative pathologies associated with Alzheimer’s disease (AD). While AD is a multifactorial disease that includes other proteinopathies (e.g., hyperphosphorylated tau aggregates) and neurotransmitter disturbances (e.g., loss of cortical cholinergic innervation), Aβ (soluble or in senile plaques) remains the major undisputed factor that contributes to the pathological and behavior presentation of AD. Overproduction of Aβ and mutations in Aβ precursor (amyloid precursor protein) or enzymes involved in Aβ1–42 production and removal (γ secretase/presenilins) have been shown in cases of early onset of AD and produced AD-like pathologies in animal models. In addition, the level of soluble Aβ1–42 has been shown to correlate with cognitive impairment in animal models before the presence of senile plaques or other histological features of AD. However, much still is unknown about the biochemical processes leading to amyloid formation and its relation to the pathogenesis, neuronal damage/dysfunction, and behavioral changes associated with AD. In this article, we review animal models that have been developed to study AD-like pathologies and then provide detailed methodology to develop an acute rat model of Aβ-induced cognitive impairment. We use this model to examine the cognitive-enhancing effect of novel pharmacological interventions targeting nicotinic acetylcholine receptors.

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References

  1. Maresova P, Mohelska H, Dolejs J, Kuca K (2015) Socio-economic aspects of Alzheimer’s disease. Curr Alzheimer Res 12:903–911

    Article  CAS  PubMed  Google Scholar 

  2. Weller J, Budson A (2008) Current understanding of Alzheimer’s disease diagnosis and treatment. F1000Res 7:1161

    Article  CAS  Google Scholar 

  3. Yiannopoulou KG, Papageorgiou SG (2013) Current and future treatments for Alzheimer’s disease. Ther Adv Neurol Disord 6:19–33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bachurin SO, Bovina EV, Ustyugov AA (2017) Drugs in clinical trials for Alzheimer’s disease: the major trends. Med Res Rev 37:1186–1225

    Article  CAS  PubMed  Google Scholar 

  5. Karran E, Mercken M, De Strooper B (2011) The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10:698–712

    Article  CAS  PubMed  Google Scholar 

  6. Zhang L, Fang Y, Xu Y, Lian Y, Xie N, Wu T, Zhang H, Sun L, Zhang R, Wang Z (2015) Curcumin improves amyloid β-peptide (1-42) induced spatial memory deficits through BDNF-ERK signaling pathway. PLoS One 10(6):e0131525

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Elder GA, Gama Sosa MA, De Gasperi R (2010) Transgenic mouse models of Alzheimer’s disease. Mt Sinai J Med 77:69–81

    Article  PubMed  PubMed Central  Google Scholar 

  8. Chin J (2011) Selecting a mouse model of Alzheimer’s disease. Methods Mol Biol 670:169–189

    Article  CAS  PubMed  Google Scholar 

  9. Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373:523–527

    Article  CAS  PubMed  Google Scholar 

  10. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274:99–102

    Article  CAS  PubMed  Google Scholar 

  11. Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, Hu K, Kholodenko D, Johnson-Wood K, McConlogue L (2000) High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 20:4050–4058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chishti MA, Yang DS, Janus C, Phinney AL, Horne P, Pearson J, Strome R, Zuker N, Loukides J, French J, Turner S, Lozza G, Grilli M, Kunicki S, Morissette C, Paquette J, Gervais F, Bergeron C, Fraser PE, Carlson GA, George-Hyslop PS, Westaway D (2001) Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695. J Biol Chem 276:21562–21570

    Article  CAS  PubMed  Google Scholar 

  13. Herzig MC, Winkler DT, Burgermeister P, Pfeifer M, Kohler E, Schmidt SD, Danner S, Abramowski D, Stürchler-Pierrat C, Bürki K, van Duinen SG, Maat-Schieman ML, Staufenbiel M, Mathews PM, Jucker M (2004) Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat Neurosci 7:954–960

    Article  CAS  PubMed  Google Scholar 

  14. Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, Ledermann B, Bürki K, Frey P, Paganetti PA, Waridel C, Calhoun ME, Jucker M, Probst A (1997) Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci U S A 94:13287–13292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rockenstein E, Hansen LA, Mallory M, Trojanowski JQ, Galasko D, Masliah E (2001) Altered expression of the synuclein family mRNA in Lewy body and Alzheimer’s disease. Brain Res 914:48–56

    Article  CAS  PubMed  Google Scholar 

  16. Cheng IH, Palop JJ, Esposito LA, Bien-Ly N, Yan F, Mucke L (2004) Aggressive amyloidosis in mice expressing human amyloid peptides with the Arctic mutation. Nat Med 10:1190–1192

    Article  CAS  PubMed  Google Scholar 

  17. Cheng IH, Scearce-Levie K, Legleiter J, Palop JJ, Gerstein H, Bien-Ly N, Puoliväli J, Lesné S, Ashe KH, Muchowski PJ, Mucke L (2007) Accelerating amyloid-beta fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models. J Biol Chem 282:23818–23828

    Article  CAS  PubMed  Google Scholar 

  18. Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-Tur J, Hutton M, Buee L, Harigaya Y, Yager D, Morgan D, Gordon MN, Holcomb L, Refolo L, Zenk B, Hardy J, Younkin S (1996) Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 383:710–713

    Article  CAS  PubMed  Google Scholar 

  19. Lee MK, Borchelt DR, Kim G, Thinakaran G, Slunt HH, Ratovitski T, Martin LJ, Kittur A, Gandy S, Levey AI, Jenkins N, Copeland N, Price DL, Sisodia SS (1997) Hyperaccumulation of FAD-linked presenilin 1 variants in vivo. Nat Med 3:756–760

    Article  CAS  PubMed  Google Scholar 

  20. Lewis J, McGowan E, Rockwood J, Melrose H, Nacharaju P, Van Slegtenhorst M, Gwinn-Hardy K, Paul Murphy M, Baker M, Yu X, Duff K, Hardy J, Corral A, Lin WL, Yen SH, Dickson DW, Davies P, Hutton M (2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 25:402–405

    Article  CAS  PubMed  Google Scholar 

  21. Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, DeTure M, Ramsden M, McGowan E, Forster C, Yue M, Orne J, Janus C, Mariash A, Kuskowski M, Hyman B, Hutton M, Ashe KH (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309:476–481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Holcomb L, Gordon MN, McGowan E, Yu X, Benkovic S, Jantzen P, Wright K, Saad I, Mueller R, Morgan D, Sanders S, Zehr C, O’Campo K, Hardy J, Prada CM, Eckman C, Younkin S, Hsiao K, Duff K (1998) Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 1:97–100

    Article  Google Scholar 

  23. Jankowskym JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, Copeland NG, Lee MK, Younkin LH, Wagner SL, Younkin SG, Borchelt DR (2004) Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet 13:159–170

    Article  Google Scholar 

  24. Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, Berry R, Vassar R (2006) Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci 26:10129–10140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L, Yager D, Eckman C, Hardy J, Hutton M, McGowan E (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293:1487–1491

    Article  CAS  PubMed  Google Scholar 

  26. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409–421

    Article  CAS  PubMed  Google Scholar 

  27. Do Carmo S, Cuello AC (2013) Modeling Alzheimer’s disease in transgenic rats. Mol Neurodegener 8:37

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Echeverria V, Ducatenzeiler A, Alhonen L, Janne J, Grant SM, Wandosell F, Muro A, Baralle F, Li H, Duff K, Szyf M, Cuello AC (2004) Rat transgenic models with a phenotype of intracellular Abeta accumulation in hippocampus and cortex. J Alzheimers Dis 6:209–219

    Article  CAS  PubMed  Google Scholar 

  29. Ruiz-Opazo N, Kosik KS, Lopez LV, Bagamasbad P, Ponce LR, Herrera VL (2004) Attenuated hippocampus-dependent learning and memory decline in transgenic TgAPPswe Fischer-344 rats. Mol Med 10:36–44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Folkesson R, Malkiewicz K, Kloskowska E, Nilsson T, Popova E, Bogdanovic N, Ganten U, Ganten D, Bader M, Winblad B, Benedikz E (2007) A transgenic rat expressing human APP with the Swedish Alzheimer’s disease mutation. Biochem Biophys Res Commun 358:777–782

    Article  CAS  PubMed  Google Scholar 

  31. Kloskowska E, Pham TM, Nilsson T, Zhu S, Oberg J, Codita A, Pedersen LA, Pedersen JT, Malkiewicz K, Winblad B, Folkesson R, Benedikz E (2010) Cognitive impairment in the Tg6590 transgenic rat model of Alzheimer’s disease. J Cell Mol Med 14:1816–1823

    Article  CAS  PubMed  Google Scholar 

  32. Leon WC, Canneva F, Partridge V, Allard S, Ferretti MT, DeWilde A, Vercauteren F, Atifeh R, Ducatenzeiler A, Klein W, Szyf M, Alhonen L, Cuello AC (2010) 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 20:113–126

    Article  CAS  PubMed  Google Scholar 

  33. Iulita MF, Bistué Millón MB, Pentz R, Aguilar LF, Do Carmo S, Allard S, Michalski B, Wilson EN, Ducatenzeiler A, Bruno MA, Fahnestock M, Cuello AC (2017) Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer’s disease. Neurobiol Dis 108:307–323

    Article  CAS  PubMed  Google Scholar 

  34. Galeano P, Leal MC, Ferrari CC, Dalmasso MC, Martino Adami PV, Farías MI, Casabona JC, Puntel M, Do Carmo S, Smal C, Arán M, Castaño EM, Pitossi FJ, Cuello AC, Morelli L (2018) Chronic hippocampal expression of notch intracellular domain induces vascular thickening, reduces glucose availability, and exacerbates spatial memory deficits in a rat model of early Alzheimer. Mol Neurobiol 55:8637–8650

    Article  CAS  PubMed  Google Scholar 

  35. Hall H, Iulita MF, Gubert P, Flores Aguilar L, Ducatenzeiler A, Fisher A, Cuello AC (2018) AF710B, an M1/sigma-1 receptor agonist with long-lasting disease-modifying properties in a transgenic rat model of Alzheimer’s disease. Alzheimers Dement 14:811–823

    Article  PubMed  Google Scholar 

  36. Flood DG, Lin YG, Lang DM, Trusko SP, Hirsch JD, Savage MJ, Scott RW, Howland DS (2009) A transgenic rat model of Alzheimer’s disease with extracellular Abeta deposition. A transgenic rat model of Alzheimer’s disease with extracellular Abeta deposition. Neurobiol Aging 30:1078–1090

    Article  CAS  PubMed  Google Scholar 

  37. Liu L, Orozco IJ, Planel E, Wen Y, Bretteville A, Krishnamurthy P, Wang L, Herman M, Figueroa H, Yu WH, Arancio O, Duff K (2008) A transgenic rat that develops Alzheimer’s disease-like amyloid pathology, deficits in synaptic plasticity and cognitive impairment. Neurobiol Dis 31:46–57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Cohen RM, Rezai-Zadeh K, Weitz TM, Rentsendorj A, Gate D, Spivak I, Bholat Y, Vasilevko V, Glabe CG, Breunig JJ, Rakic P, Davtyan H, Agadjanyan MG, Kepe V, Barrio JR, Bannykh S, Szekely CA, Pechnick RN, Town T (2013) A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric aβ, and frank neuronal loss. J Neurosci 33:6245–6256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Filipcik P, Zilka N, Bugos O, Kucerak J, Koson P, Novak P, Novak M (2012) First transgenic rat model developing progressive cortical neurofibrillary tangles. Neurobiol Aging 33:1448–1456

    Article  PubMed  Google Scholar 

  40. Hilliard WG, Dillistone EJ, Oliver WT (1968) A method for cerebroventricular cannulation of the rat. Can J Comp Med Vet Sci 32:368–371

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Paxinos G, Watson C (2004) The rat brain in stereotaxic coordinates – the new coronal set, 5th edn. Academic Press, New York

    Google Scholar 

  42. Stine WB, Jungbauer L, Yu C, LaDu MJ (2011) Preparing synthetic Aβ in different aggregation states. Methods Mol Biol 670:13–32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Colaianna M, Tucci P, Zotti M, Morgese MG, Schiavone S, Govoni S, Cuomo V, Trabace L (2010) Soluble beta amyloid(1–42): a critical player in producing behavioural and biochemical changes evoking depressive-related state? Br J Pharmacol 159:1704–1715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Shiotsuki H, Yoshimi K, Shimo Y, Funayama M, Takamatsu Y, Ikeda K, Takahashi R, Kitazawa S, Hattori N (2010) A rotarod test for evaluation of motor skill learning. J Neurosci Methods 189:180–185

    Article  PubMed  Google Scholar 

  45. Jarrard LE, Okaichi H, Steward O, Goldschmidt RB (1984) On the role of hippocampal connections in the performance of place and cue tasks: comparisons with damage to hippocampus. Behav Neurosci 98:946–954

    Article  CAS  PubMed  Google Scholar 

  46. Ahmadalipour A, Sadeghzadeh J, Vafaei AA, Bandegi AR, Mohammadkhani R, Rashidy-Pour A (2015) Effects of environmental enrichment on behavioral deficits and alterations in hippocampal BDNF induced by prenatal exposure to morphine in juvenile rats. Neuroscience 305:372–383

    Article  CAS  PubMed  Google Scholar 

  47. Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11:47–60

    Article  CAS  PubMed  Google Scholar 

  48. Vorhees CV, Williams MT (2006) Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1:848–858

    Article  PubMed  PubMed Central  Google Scholar 

  49. Mura E, Zappettini S, Preda S, Biundo F, Lanni C, Grilli M, Cavallero A, Olivero G, Salamone A, Govoni S, Marchi M (2012) Dual effect of beta-amyloid on α7 and α4β2 nicotinic receptors controlling the release of glutamate, aspartate and GABA in rat hippocampus. PLoS One 7:e29661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

A.K.H. is supported by The University of Texas System Rising STARs Program Fund.

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Authors and Affiliations

  1. Department of Pharmaceutical Science, Fisch College of Pharmacy, University of Texas at Tyler, Tyler, TX, USA

    Farah Deba & Ayman K. Hamouda

  2. Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University, Kingsville, TX, USA

    Steven Peterson

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  1. Farah Deba
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  2. Steven Peterson
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  3. Ayman K. Hamouda
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Corresponding authors

Correspondence to Steven Peterson or Ayman K. Hamouda .

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Editors and Affiliations

  1. Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon

    Firas H. Kobeissy

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Deba, F., Peterson, S., Hamouda, A.K. (2019). An Animal Model to Test Reversal of Cognitive Decline Associated with Beta-Amyloid Pathologies. In: Kobeissy, F. (eds) Psychiatric Disorders. Methods in Molecular Biology, vol 2011. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9554-7_23

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  • DOI: https://doi.org/10.1007/978-1-4939-9554-7_23

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  • Publisher Name: Humana, New York, NY

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