Aggregation, impaired degradation and immunization targeting of amyloid-beta dimers in Alzheimer’s disease: a stochastic modelling approach

Molecular Neurodegeneration

Thomas BL Kirkwood²  Joanna L Elson¹  Ilse Sanet Pienaar²  Carole J Proctor² 

[1] Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, United Kingdom;Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL, United Kingdom

关键词: Stochastic simulation;    Protein aggregation;    Mathematical model;    Immunotherapy;    Intervention;    Down’s syndrome;    Dimers;    Amyloid-beta;    Alzheimer’s disease;   

Others  :  863795
DOI  :  10.1186/1750-1326-7-32

 received in 2012-03-02, accepted in 2012-06-11,  发布年份 2012

【 摘 要 】

Background

Alzheimer’s disease (AD) is the most frequently diagnosed neurodegenerative disorder affecting humans, with advanced age being the most prominent risk factor for developing AD. Despite intense research efforts aimed at elucidating the precise molecular underpinnings of AD, a definitive answer is still lacking. In recent years, consensus has grown that dimerisation of the polypeptide amyloid-beta (Aß), particularly Aß₄₂, plays a crucial role in the neuropathology that characterise AD-affected post-mortem brains, including the large-scale accumulation of fibrils, also referred to as senile plaques. This has led to the realistic hope that targeting Aß₄₂ immunotherapeutically could drastically reduce plaque burden in the ageing brain, thus delaying AD onset or symptom progression. Stochastic modelling is a useful tool for increasing understanding of the processes underlying complex systems-affecting disorders such as AD, providing a rapid and inexpensive strategy for testing putative new therapies. In light of the tool’s utility, we developed computer simulation models to examine Aß₄₂ turnover and its aggregation in detail and to test the effect of immunization against Aß dimers.

Results

Our model demonstrates for the first time that even a slight decrease in the clearance rate of Aß₄₂ monomers is sufficient to increase the chance of dimers forming, which could act as instigators of protofibril and fibril formation, resulting in increased plaque levels. As the process is slow and levels of Aβ are normally low, stochastic effects are important. Our model predicts that reducing the rate of dimerisation leads to a significant reduction in plaque levels and delays onset of plaque formation. The model was used to test the effect of an antibody mediated immunological response. Our results showed that plaque levels were reduced compared to conditions where antibodies are not present.

Conclusion

Our model supports the current thinking that levels of dimers are important in initiating the aggregation process. Although substantial knowledge exists regarding the process, no therapeutic intervention is on offer that reliably decreases disease burden in AD patients. Computer modelling could serve as one of a number of tools to examine both the validity of reliable biomarkers and aid the discovery of successful intervention strategies.

【 授权许可】

   
2012 Proctor et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Selkoe DJ: Alzheimer’s disease is a synaptic failure. Science 2002, 298(5594):789-791.
• [2]Braak H, Braak E: Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991, 82(4):239-259.
• [3]Foundas AL, Leonard CM, Mahoney SM, Agee OF, Heilman KM: Atrophy of the hippocampus, parietal cortex, and insula in Alzheimer's disease: a volumetric magnetic resonance imaging study. Neuropsychiatry, neuropsychology, and behavioral neurology 1997, 10(2):81-89.
• [4]Armstrong RA: Plaques and tangles and the pathogenesis of Alzheimer's disease. Folia neuropathologica/Association of Polish Neuropathologists and Medical Research Centre, Polish Academy of Sciences 2006, 44(1):1-11.
• [5]Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT: Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology 1992, 42(3 Pt 1):631-639.
• [6]Verdile G, Fuller S, Atwood CS, Laws SM, Gandy SE, Martins RN: The role of beta amyloid in Alzheimer’s disease: still a cause of everything or the only one who got caught? Pharmacological Research 2004, 50(4):397-409.
• [7]Hardy J: Amyloid, the presenilins and Alzheimer's disease. Trends Neurosci 1997, 20(4):154-159.
• [8]Fukumoto H, Asami-Odaka A, Suzuki N, Shimada H, Ihara Y, Iwatsubo T: Amyloid beta protein deposition in normal aging has the same characteristics as that in Alzheimer’s disease. Predominance of A beta 42(43) and association of A beta 40 with cored plaques. Am J Pathol 1996, 148(1):259-265.
• [9]Wisniewski KE, Wisniewski HM, Wen GY: Occurrence of neuropathological changes and dementia of Alzheimer's disease in Down's syndrome. Ann Neurol 1985, 17(3):278-282.
• [10]St George-Hyslop PH, Tanzi RE, Polinsky RJ, Haines JL, Nee L, Watkins PC, Myers RH, Feldman RG, Pollen D, Drachman D, et al.: The genetic defect causing familial Alzheimer's disease maps on chromosome 21. Science 1987, 235(4791):885-890.
• [11]Coppus AM, Schuur M, Vergeer J, Janssens AC, Oostra BA, Verbeek MM, van Duijn CM: Plasma beta amyloid and the risk of Alzheimer's disease in Down syndrome. Neurobiol Aging 2012, 33:1988. http://dx.doi.org/10.1016/j.neurobiolaging webcite.2011.08.007
• [12]Walsh DM, Lomakin A, Benedek GB, Condron MM, Teplow DB: Amyloid beta-protein fibrillogenesis. Detection of a protofibrillar intermediate. The Journal of biological chemistry 1997, 272(35):22364-22372.
• [13]Lomakin A, Teplow DB, Kirschner DA, Benedek GB: Kinetic theory of fibrillogenesis of amyloid beta-protein. Proc Natl Acad Sci U S A 1997, 94(15):7942-7947.
• [14]Eisenberg D, Jucker M: The amyloid state of proteins in human diseases. Cell 2012, 148(6):1188-1203.
• [15]Klein WL, Krafft GA, Finch CE: Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum? Trends Neurosci 2001, 24(4):219-224.
• [16]Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, et al.: Amyloid-b protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med 2008, 14(8):837-842.
• [17]Klyubin I, Betts V, Welzel AT, Blennow K, Zetterberg H, Wallin A, Lemere CA, Cullen WK, Peng Y, Wisniewski T, et al.: Amyloid beta protein dimer-containing human CSF disrupts synaptic plasticity: prevention by systemic passive immunization. J Neurosci 2008, 28(16):4231-4237.
• [18]Mc Donald JM, Savva GM, Brayne C, Welzel AT, Forster G, Shankar GM, Selkoe DJ, Ince PG, Walsh DM: The presence of sodium dodecyl sulphate-stable Aβ dimers is strongly associated with Alzheimer-type dementia. Brain 2010, 133(5):1328-1341.
• [19]O'Nuallain B, Freir DB, Nicoll AJ, Risse E, Ferguson N, Herron CE, Collinge J, Walsh DM: Amyloid beta-protein dimers rapidly form stable synaptotoxic protofibrils. J Neurosci 2010, 30(43):14411-14419.
• [20]O'Nuallain B, Klyubin I, Mc Donald JM, Foster JS, Welzel A, Barry A, Dykoski RK, Cleary JP, Gebbink MF, Rowan MJ, et al.: A monoclonal antibody against synthetic Abeta dimer assemblies neutralizes brain-derived synaptic plasticity-disrupting Abeta. J Neurochem 2011, 119(1):189-201.
• [21]Bates KA, Verdile G, Li QX, Ames D, Hudson P, Masters CL, Martins RN: Clearance mechanisms of Alzheimer's amyloid-[beta] peptide: implications for therapeutic design and diagnostic tests. Mol Psychiatry 2008, 14(5):469-486.
• [22]Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, Yarasheski KE, Bateman RJ: Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science 2010, 330(6012):1774.
• [23]Hellstrom-Lindahl E, Ravid R, Nordberg A: Age-dependent decline of neprilysin in Alzheimer's disease and normal brain: inverse correlation with A beta levels. Neurobiol Aging 2008, 29(2):210-221.
• [24]Russo R, Borghi R, Markesbery W, Tabaton M, Piccini A: Neprylisin decreases uniformly in Alzheimer's disease and in normal aging. FEBS Lett 2005, 579(27):6027-6030.
• [25]Wang D-S, Iwata N, Hama E, Saido TC, Dickson DW: Oxidized neprilysin in aging and Alzheimer’s disease brains. Biochemical and Biophysical Research Communications 2003, 310(1):236-241.
• [26]Miners JS, van Helmond Z, Kehoe PG, Love S: Changes with age in the activities of beta-secretase and the Abeta-degrading enzymes neprilysin, insulin-degrading enzyme and angiotensin-converting enzyme. Brain pathology (Zurich, Switzerland) 2010, 20(4):794-802.
• [27]Miners JS, Baig S, Tayler H, Kehoe PG, Love S: Neprilysin and insulin-degrading enzyme levels are increased in Alzheimer disease in relation to disease severity. J Neuropathol Exp Neurol 2009, 68(8):902-914.
• [28]Miners JS, Barua N, Kehoe PG, Gill S, Love S: Abeta-degrading enzymes: potential for treatment of Alzheimer disease. J Neuropathol Exp Neurol 2011, 70(11):944-959.
• [29]Proctor C, Gray D: GSK3 and p53 - is there a link in Alzheimer's disease? Molecular Neurodegeneration 2010, 5(1):7. BioMed Central Full Text
• [30]McAuley MT, Kenny RA, Kirkwood TB, Wilkinson DJ, Jones JJ, Miller VM: A mathematical model of aging-related and cortisol induced hippocampal dysfunction. BMC neuroscience 2009, 10:26. BioMed Central Full Text
• [31]Proctor CJ, Lorimer IA: Modelling the role of the Hsp70/Hsp90 system in the maintenance of protein homeostasis. PLoS ONE 2011, 6(7):e22038.
• [32]Kirkwood TB: A systematic look at an old problem. Nature 2008, 451(7179):644-647.
• [33]Zhang J, Liu XY: Effect of protein–protein interactions on protein aggregation kinetics. The Journal of Chemical Physics 2003, 119(20):10972-10976.
• [34]Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH: A specific amyloid-beta protein assembly in the brain impairs memory. Nature 2006, 440(7082):352-357.
• [35]Busche MA, Chen X, Henning HA, Reichwald J, Staufenbiel M, Sakmann B, Konnerth A: Critical role of soluble amyloid-beta for early hippocampal hyperactivity in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A 2012, 109(22):8740-8745.
• [36]Lambert MP, Velasco PT, Chang L, Viola KL, Fernandez S, Lacor PN, Khuon D, Gong Y, Bigio EH, Shaw P, et al.: Monoclonal antibodies that target pathological assemblies of Abeta. J Neurochem 2007, 100(1):23-35.
• [37]Lemere CA, Beierschmitt A, Iglesias M, Spooner ET, Bloom JK, Leverone JF, Zheng JB, Seabrook TJ, Louard D, Li D, et al.: Alzheimer's disease abeta vaccine reduces central nervous system abeta levels in a non-human primate, the Caribbean vervet. Am J Pathol 2004, 165(1):283-297.
• [38]Lemere CA: Developing novel immunogens for a safe and effective Alzheimer's disease vaccine. Progress in brain research 2009, 175:83-93.
• [39]Basi G, Hemphill S, Brigham E, Liao A, Aubele D, Baker J, Barbour R, Bova M, Chen X-H, Dappen M, et al.: Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease. Alzheimer's research & therapy 2010, 2(6):36. BioMed Central Full Text
• [40]Bennett DA, Schneider JA, Arvanitakis Z, Kelly JF, Aggarwal NT, Shah RC, Wilson RS: Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology 2006, 66(12):1837-1844.
• [41]Giannakopoulos P, Herrmann FR, Bussiere T, Bouras C, Kovari E, Perl DP, Morrison JH, Gold G, Hof PR: Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer's disease. Neurology 2003, 60(9):1495-1500.
• [42]Price JL, Davis PB, Morris JC, White DL: The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer's disease. Neurobiol Aging 1991, 12(4):295-312.
• [43]Adalbert R, Nogradi A, Babetto E, Janeckova L, Walker SA, Kerschensteiner M, Misgeld T, Coleman MP: Severely dystrophic axons at amyloid plaques remain continuous and connected to viable cell bodies. Brain 2009, 132(2):402-416.
• [44]Serrano-Pozo A, William CM, Ferrer I, Uro-Coste E, Delisle M-B, Maurage C-A, Hock C, Nitsch RM, Masliah E, Growdon JH, et al.: Beneficial effect of human anti-amyloid-b active immunization on neurite morphology and tau pathology. Brain 2010, 133(5):1312-1327.
• [45]Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA: Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993, 261(5123):921-923.
• [46]Bu G: Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy. Nat Rev Neurosci 2009, 10(5):333-344.
• [47]Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, Reddy PH: Mitochondria are a direct site of Aβ accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression. Human Molecular Genetics 2006, 15(9):1437-1449.
• [48]Miners JS, Kehoe P, Love S: Neprilysin Protects against Cerebral Amyloid Angiopathy and Aβ-Induced Degeneration of Cerebrovascular Smooth Muscle Cells. Brain Pathology 2011, 21(5):594-605.
• [49]Cruz L, Urbanc B, Buldyrev SV, Christie R, Gómez-Isla T, Havlin S, McNamara M, Stanley HE, Hyman BT: Aggregation and disaggregation of senile plaques in Alzheimer disease. Proceedings of the National Academy of Sciences 1997, 94(14):7612-7616.
• [50]Lomakin A, Chung DS, Benedek GB, Kirschner DA, Teplow DB: On the nucleation and growth of amyloid beta-protein fibrils: detection of nuclei and quantitation of rate constants. Proc Natl Acad Sci U S A 1996, 93(3):1125-1129.
• [51]Soreghan B, Kosmoski J, Glabe C: Surfactant properties of Alzheimer's A beta peptides and the mechanism of amyloid aggregation. Journal of Biological Chemistry 1994, 269(46):28551-28554.
• [52]Hucka M, Finney A, Sauro HM, Bolouri H, Doyle JC, Kitano H, Arkin AP, Bornstein BJ, Bray D, and the rest of the SBML Forum: The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models. Bioinformatics 2003, 19(4):524-531.
• [53]Wilkinson DJ: Stochastic modelling for systems biology. second edition. Chapman and Hall/CRC Press, Boca Raton, Florida; 2011.
• [54]Grasbon-Frodl EM, Kösel S, Sprinzl M, von Eitzen U, Mehraein P, Graeber MB: Two novel point mutations of mitochondrial tRNA genes in histologically confirmed Parkinson disease. Neurogenetics 1999, 2(2):121-127.
• [55]Biomodels Database [http://www.ebi.ac.uk/biomodels]
• [56]The Systems Biology Markup Language [www.sbml.org]
• [57]Gillespie DT: Exact stochastic simulation of coupled chemical reactions. The Journal of Physical Chemistry 1977, 31:2340-2361.