LOGIN TO YOUR ACCOUNT

Username
Password
Remember Me
Or use your Academic/Social account:

CREATE AN ACCOUNT

Or use your Academic/Social account:

Congratulations!

You have just completed your registration at OpenAire.

Before you can login to the site, you will need to activate your account. An e-mail will be sent to you with the proper instructions.

Important!

Please note that this site is currently undergoing Beta testing.
Any new content you create is not guaranteed to be present to the final version of the site upon release.

Thank you for your patience,
OpenAire Dev Team.

Close This Message

CREATE AN ACCOUNT

Name:
Username:
Password:
Verify Password:
E-mail:
Verify E-mail:
*All Fields Are Required.
Please Verify You Are Human:
fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Falinska, Agnieszka Malgorzata
Languages: English
Types: Doctoral thesis
Subjects:
Alzheimer's disease, the most common type of senile dementia, is characterised by p-amyloid plaques, neurofibrillary tangles and neuronal loss. Amyloid plaques are associated with the increased inflammation and oxidative stress. Rodent models overexpressing APP are a useful tool to investigate both the processes and the consequences of amyloid generation, and are crucial for developing and testing hypotheses about treatments and risk factors. Tg2576 transgenic mice overexpress human 'Swedish' mutated APP and show memory impairment followed by amyloid plaques pathology. GP56 rats also overexpress human 'Swedish' mutated APP, but show no signs of AD-like pathology. In this thesis, I explored the influence of dietary and pharmacological modifications on pathogenesis of AD as tested in rodent models. As epidemiological data implicated the role of non-steroidal anti-inflammatory drugs (NSAIDs) in reducing the risk of AD, I investigated the role of ibuprofen as either prevention or treatment in transgenic mice. The results indicated that ibuprofen delayed the onset of behavioural impairment but only when it was administered early during the evolution of their pathology. Levels of Ap and plaque pathology were not affected. Also consumption of n-3 fatty acids seemed to reduce the risk of AD, possibly by acting as an anti-oxidant. Thus I investigated the effect of DHA on learning ability and pathology in AD mice. Administration of DHA to young mice reduced the impairment in learning but did not alter Ap levels or plaque pathology. Finally the role of high cholesterol diet was investigated in GP56 rats. Feeding rats for 8 weeks did not induce any amyloid-connected pathology. The results indicate that modulation of inflammatory processes, or lipids can have modest ameliorating effects on behavioural impairments in rodent AD models, provided intervention is undertaken early, but suggest these may not be the most efficacious targets for therapeutic intervention.
  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • 2 C hapter 2 G eneral methods 2.1 Behavioural testing 2.1.1 Forced Choice Alternation Task in the T-maze 2.1.2 Morris Water Maze, Reference Memory 2.2 Electrophysiological studies of hippocampus in vivo 2.3 ELISA - Enzyme Linked-Immuno-Sorbent Assay 2.4 Immunohistochemistry - paraffin wax sections Boutaud,0, J J Ou, P Chaurand, R M Caprioli, T J Montine, J A Oates, 2002, Prostaglandin H2 (PGH2) accelerates formation o f amyloid betal-42 oligomers: J.Neurochem., v. 82, p. 1003-1006.
    • Braak,H, E Braak, 1995, Staging o f Alzheimer's disease-related neurofibrillary changes: Neurobiol. Aging, v. 16, p. 271-278.
    • Brayne,C, C Gill, F A Huppert, C Barkley, E Gehlhaar, D M Girling, D W O'Connor, E S Paykel, 1998, Vascular risks and incident dementia: results from a cohort study o f the very old: Dement.Geriatr.Cogn Disord., v. 9, p. 175-180.
    • Breitner,JC, K A Welsh, M J Helms, P C Gaskell, B A Gau, A D Roses, M A Pericak-Vance, A M Saunders, 1995, Delayed onset o f Alzheimer's disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs: Neurobiol. Aging, v. 16, p. 523-530.
    • Brookmeyer,R, S Gray, C Kawas, 1998, Projections o f Alzheimer's disease in the United States and the public health impact o f delaying disease onset: Am.J.Public Health, v. 88, p. 1337-1342.
    • Buee,L, T Bussiere, V Buee-Scherrer, A Delacourte, P R Hof, 2000, Tau protein isoforms, phosphorylation and role in neurodegenerative disorders: Brain Res.Brain Res.Rev., v. 33, p. 95-130.
    • Bums,MP, W J Noble, V Olm, K Gaynor, E Casey, J LaFrancois, L Wang, K Duff, 2003, Co-localization o f cholesterol, apolipoprotein E and fibrillar Abeta in amyloid plaques: Brain Res.Mol.Brain R es., v. 110, p.
    • Butterfield,DA, K Hensley, M Harris, M Mattson, J Carney, 1994, beta-Amyloid peptide free radical fragments initiate synaptosomal lipoperoxidation in a sequence-specific fashion: implications to Alzheimer's disease: Biochem.Biophys.Res.Commun., v. 200, p. 710-715.
    • Calder,PC, 2003, N ew evidence in support o f the cardiovascular benefit o f long-chain n-3 fatty acids: Ital.Heart J., v. 4, p. 427-429.
    • Calhoun,ME, K H Wiederhold, D Abramowski, A L Phinney, A Probst, C Sturchler-Pierrat, M Staufenbiel, B Sommer, M Jucker, 1998, Neuron loss in APP transgenic mice: Nature, v. 395, p. 755-756.
    • Campion,D, J M Flaman, A Brice, D Hannequin, B Dubois, C Martin, V Moreau, F Charbonnier, O Didieijean, S Tardieu,., 1995, Mutations o f the presenilin I gene in families with early-onset Alzheimer's disease: Hum.Mol.Genet., v. 4, p. 2373-2377.
    • Campion,D, C Dumanchin, D Hannequin, B Dubois, S Belliard, M Puel, C Thomas-Anterion, A Michon, C Martin, F Charbonnier, G Raux, A Camuzat, C Penet, V Mesnage, M Martinez, F Clerget-Darpoux, A Brice, T Frebourg, 1999, Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum: Am. J.Hum.Genet., v. 65, p. 664-670.
    • Carlson,GA, D R Borchelt, A Dake, S Turner, V Danielson, J D Coffin, C Eckman, J Meiners, S P Nilsen, S G Younkin, K K Hsiao, 1997, Genetic modification o f the phenotypes produced by amyloid precursor protein overexpression in transgenic mice: Hum.Mol.Genet., v. 6, p. 1951-1959.
    • Casper,D, U Yaparpalvi, N Rempel, P Werner, 2000, Ibuprofen protects dopaminergic neurons against glutamate toxicity in vitro: Neurosci.Lett., v. 289, p. 201-204.
    • Chalon,S, S Delion-Vancassel, C Belzung, D Guilloteau, A M Leguisquet, J C Besnard, G Durand, 1998, Dietary fish oil affects monoaminergic neurotransmission and behavior in rats: J.Nutr., v. 128, p. 2512- 2519.
    • Cutter,WJ, M Craig, R Noibury, D M Robertson, M Whitehead, D G Murphy, 2003, In vivo effects o f estrogen on human brain: Ann.N.Y.Acad.Sci., v. 1007, p. 79-88.
    • D'Hooge,R, P P D e Deyn, 2001, Applications o f the Morris water maze in the study o f learning and memory: Brain Res.Brain Res.Rev., v. 36, p. 60-90.
    • Das,UN, 2002, The lipids that matter from infant nutrition to insulin resistance: Prostaglandins Leukot.Essent.Fatty Acids, v. 67, p. 1-12.
    • Das,UN, Fams, 2003, Long-chain polyunsaturated fatty acids in the growth and development o f the brain and memory: Nutrition, v. 19, p. 62-65.
    • Davis S, Butcher SP, Morris RG. The NM D A receptor antagonist D-2-amino-5-phosphonopentanoate (DAP5) impairs spatial learning and LTP in vivo at intracerebral concentrations comparable to those that block LTP in vitro. JNeurosci 1992;12:21-34.
    • Davis,DG, F A Schmitt, D R Wekstein, W R Markesbery, 1999, Alzheimer neuropathologic alterations in aged cognitively normal subjects: J.Neuropathol.Exp Neurol., v. 58, p. 376-388.
    • de la Torre,JC, 1999, Critical threshold cerebral hypoperfusion causes Alzheimer's disease?: Acta Neuropathol.(Berl), v. 98, p. 1-8.
    • Delerive,P, J C Fruchart, B Staels, 2001, Peroxisome proliferator-activated receptors in inflammation control: J.Endocrinol., v. 169, p. 453-459.
    • Delion, S, S Chalon, D Guilloteau, J C Besnard, G Durand, 1996, alpha-Linolenic acid dietary deficiency alters age-related changes o f dopaminergic and serotoninergic neurotransmission in the rat frontal cortex: J.Neurochem., v. 66, p. 1582-1591.
    • Delion,S, S Chalon, D Guilloteau, B Lejeune, J C Besnard, G Durand, 1997, Age-related changes in phospholipid fatty acid composition and monoaminergic neurotransmission in the hippocampus o f rats fed a balanced or an n-3 polyunsaturated fatty acid-deficient diet: J.Lipid Res., v. 38, p. 680-689.
    • Dietschy,JM, S D Turley, 2001, Cholesterol metabolism in the brain: Curr.Opin.Lipidol., v. 12, p. 105-112.
    • Dodart,JC, H Meziane, C Mathis, K R Bales, S M Paul, A Ungerer, 1999, Behavioral disturbances in transgenic mice overexpressing the V717F beta-amyloid precursor protein: Behav.Neurosci., v. 113, p. 982- 990.
    • Dodart,JC, K R Bales, K S Gannon, S J Greene, R B DeMattos, C Mathis, C A DeLong, S Wu, X Wu, D M Holtzman, S M Paul, 2002, Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model: Nat.Neurosci., v. 5, p. 452-457.
    • Gouras,GK, J Tsai, J Naslund, B Vincent, M Edgar, F Checler, J P Greenfield, V Haroutunian, J D Buxbaum, H Xu, P Greengard, N R Relkin, 2000, Intraneuronal Abeta42 accumulation in human brain: Am.J.Pathol., v. 156, p. 15-20.
    • Grant,WB, A Campbell, R F Itzhaki, J Savory, 2002, The significance o f environmental factors in the etiology o f Alzheimer's disease: J.Alzheimers.Dis., v. 4, p. 179-189.
    • Greeve,I, D Kretzschmar, J A Tschape, A Beyn, C Brellinger, M Schweizer, R M Nitsch, R Reifegerste, 2004, Age-dependent neurodegeneration and Alzheimer-amyloid plaque formation in transgenic Drosophila: J.Neurosci., v. 24, p. 3899-3906.
    • Guillozet,AL, S Weintraub, D C Mash, M M Mesulam, 2003, Neurofibrillary tangles, amyloid, and memory in aging and mild cognitive impairment: Arch.Neurol., v. 60, p. 729-736.
    • Haag,M, 2003, Essential fatty acids and the brain: Can.J.Psychiatry, v. 48, p. 195-203.
    • Haass,C, E H Koo, A Mellon, A Y Hung, D J Selkoe, 1992, Targeting o f cell-surface beta-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments: Nature, v. 357, p.
    • Halliwell,B, 1992, Reactive oxygen species and the central nervous system: J.Neurochem., v. 59, p. 1609- 1623.
    • Halliwell,B, 1997, Antioxidants and human disease: a general introduction: Nutr.Rev., v. 55, p. S44-S49.
    • Halliwell,B, 1999, Antioxidant defence mechanisms: from the beginning to the end (o f the beginning): Free Radic.Res., v. 31, p. 261-272.
    • Hamdane,M, P Delobel, A V Sambo, C Smet, S Begard, A Violleau, I Landrieu, A Delacourte, G Lippens, S Flament, L Buee, 2003, Neurofibrillary degeneration o f the Alzheimer-type: an alternate pathway to neuronal apoptosis?: Biochem.Pharmacol., v. 66, p. 1619-1625.
    • Hansen,HS, 1994, N ew biological and clinical roles for the n-6 and n-3 fatty acids: Nutr.Rev., v. 52, p. 162- 167.
    • Hardy,JA, G A Higgins, 1992, Alzheimer's disease: the amyloid cascade hypothesis: Science, v. 256, p.
    • Hashimoto,M, S Hossain, T Shimada, K Sugioka, H Yamasaki, Y Fujii, Y Ishibashi, J Oka, O Shido, 2002, Docosahexaenoic acid provides protection from impairment o f learning ability in Alzheimer's disease model rats: J.Neurochem., v. 81, p. 1084-1091.
    • Hauss-Wegrzyniak,B, P Dobrzanski, J D Stoehr, G L Wenk, 1998, Chronic neuroinflammation in rats reproduces components o f the neurobiology o f Alzheimer's disease: Brain Res., v. 780, p. 294-303.
    • Hauss-Wegrzyniak,B, P Vraniak, G L Wenk, 1999, The effects o f a novel NSAID on chronic neuroinflammation are age dependent: Neurobiol.Aging, v. 20, p. 305-313.
    • Hauss-Wegrzyniak,B, P D Vraniak, G L Wenk, 2000, LPS-induced neuroinflammatory effects do not recover with time: Neuroreport, v. 11, p. 1759-1763.
    • Hauss-Wegrzyniak,B, M A Lynch, P D Vraniak, G L Wenk, 2002, Chronic brain inflammation results in cell loss in the entorhinal cortex and impaired LTP in perforant path-granule cell synapses: Exp.Neurol., v.
    • 176, p. 336-341.
    • Hebert,LE, P A Scherr, J L Bienias, D A Bennett, D A Evans, 2003, Alzheimer disease in the US population: prevalence estimates using the 2000 census: Arch.Neurol., v. 60, p. 1119-1122.
    • Mizuno,T, M Nakata, H Naiki, M Michikawa, R Wang, C Haass, K Yanagisawa, 1999, Cholesteroldependent generation o f a seeding amyloid beta-protein in cell culture: J.Biol.Chem., v. 274, p. 15110- 15114.
    • 1. Lee JH, Lau KF, Perkinton MS, Standen CL, Rogelj B, Falinska A, McLoughlin DM, Miller CC (2004). The neuronal adaptor protein X llbeta reduces Abeta levels and amyloid plaque formation in the brains of transgenic mice. J Biol Chem. 2004 Sep 3 2. Chapman PF, Falinska AM, Knevett SG, Ramsay MF (2001). Genes, models and Alzheimer's disease. Trends Genet 2001 May; 17(5): 254-61 3. Westerman MA, Kotilinek LA, Lim GP, Falinska AM, Younkin LH, Cleary J, Chapman PF, Younkin SG, Frautschy SA, Cole GM, Ashe KH. “Restoration of memory by NSAIDs in a mouse model of Alzheimer's disease”. Paper submitted to Neuron (2004).
    • 1. AM Falinska; V.J. Marshall; P.F. Chapman “The effects of high-cholesterol diet on behaviour and synaptic physiology in APP transgenic rats”. Society for Neuroscience 32nd Annual Meeting in Orlando, November 2-7,20 02 2. AM Falinska; A.S. Yates; P.F. Chapman “The effects of chronic ibuprofen treatment on learning and memory in APP transgenic mice”. Society for Neuroscience's 31st Annual Meeting San Diego, CA November 10-15,2001 3. “NSAIDs as a potential treatment for Alzheimer Disease” a seminar presented at the Department of Medical Biochemistry, University of Wales College of Medicine, Cardiff, June 2002 4. “Effects of anti-inflammatory agents on memory in Tg2576 mice” a talk presented at The Biology of Alzheimer's Disease in Transgenic Mice - The Third Meeting, San Diego, California, Nov 2001
  • Inferred research data

    The results below are discovered through our pilot algorithms. Let us know how we are doing!

    Title Trust
    40
    40%
  • No similar publications.

Share - Bookmark

Cite this article