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Table of Contents
Vol. 8, No. 5, 2011
Issue release date: June 2011
Neurodegenerative Dis 2011;8:352–363
(DOI:10.1159/000323871)

Characterization of the Brain β-Amyloid Isoform Pattern at Different Ages of Tg2576 Mice

Mustafiz T. · Portelius E. · Gustavsson M.K. · Hölttä M. · Zetterberg H. · Blennow K. · Nordberg A. · Unger Lithner C.
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Abstract

Background: Although genetic and biochemical studies have suggested a cardinal role for β-amyloid (Aβ) in Alzheimer’s disease, the underlying mechanism(s) of how Aβ induces neurodegeneration is still unclear. Our objective was to investigate the consequences of Aβ, especially on tau phosphorylation at specific epitopes important for Alzheimer’s disease. Methods: We used cortices from Tg2576 mice at 7 days to 15 months of age. Results: MALDI-TOF MS revealed an age-dependent shift in the Aβ isoform pattern. Young animals displayed high cortical levels of the shorter Aβ isoforms (Aβ1–16 and Aβ1–17) compared to 15-month-old Tg2576 mice which mainly expressed Aβ1–40 and Aβ1–42. The Aβ1–42 showed an age-dependent increase, whereas total Aβ1–40 levels remained constant. The highest levels of TBS-soluble Aβ oligomers were found at 90 days of age. Brain Aβ build-up did not affect the phosphorylation of tau at the epitopes investigated. Conclusions: This study provides new information about age-dependent Aβ isoforms and oligomers as well as their effect on site-specific tau phosphorylation in this transgenic mouse model. Our observations suggest that the different human Aβ isoforms do not directly cause increased tau phosphorylation and that the cognitive deficits seen in this mouse model are only related to the Aβ overexpression.



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References

  1. Roher A, Wolfe D, Palutke M, KuKuruga D: Purification, ultrastructure, and chemical analysis of Alzheimer disease amyloid plaque core protein. Proc Natl Acad Sci USA 1986;83:2662–2666.
  2. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI: Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 1986;83:4913–4917.
  3. Hardy J, Selkoe DJ: The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002;297:353–356.
  4. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ: Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 2002;416:535–539.
  5. Gong Y, Chang L, Viola KL, Lacor PN, Lambert MP, Finch CE, Krafft GA, Klein WL: Alzheimer’s disease-affected brain: presence of oligomeric a beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci USA 2003;100:10417–10422.
  6. 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;440:352–357.
  7. Barghorn S, Nimmrich V, Striebinger A, Krantz C, Keller P, Janson B, Bahr M, Schmidt M, Bitner RS, Harlan J, Barlow E, Ebert U, Hillen H: Globular amyloid beta-peptide oligomer – a homogenous and stable neuropathological protein in Alzheimer’s disease. J Neurochem 2005;95:834–847.
  8. Harper JD, Wong SS, Lieber CM, Lansbury PT: Observation of metastable Abeta amyloid protofibrils by atomic force microscopy. Chem Biol 1997;4:119–125.
  9. Liu F, Grundke-Iqbal I, Iqbal K, Gong CX: Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur J Neurosci 2005;22:1942–1950.
  10. Iqbal K, Zaidi T, Bancher C, Grundke-Iqbal I: Alzheimer paired helical filaments. Restoration of the biological activity by dephosphorylation. FEBS Lett 1994;349:104–108.
  11. Atzori C, Ghetti B, Piva R, Srinivasan AN, Zolo P, Delisle MB, Mirra SS, Migheli A: Activation of the JNK/p38 pathway occurs in diseases characterized by tau protein pathology and is related to tau phosphorylation but not to apoptosis. J Neuropathol Exp Neurol 2001;60:1190–1197.
  12. Buee L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR: Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev 2000;33:95–130.
  13. Ferrer I, Pastor P, Rey MJ, Munoz E, Puig B, Pastor E, Oliva R, Tolosa E: Tau phosphorylation and kinase activation in familial tauopathy linked to deln296 mutation. Neuropathol Appl Neurobiol 2003;29:23–34.
  14. 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;42:631–639.
  15. Irizarry MC, Soriano F, McNamara M, Page KJ, Schenk D, Games D, Hyman BT: Abeta deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. J Neurosci 1997;17:7053–7059.
  16. Westerman MA, Cooper-Blacketer D, Mariash A, Kotilinek L, Kawarabayashi T, Younkin LH, Carlson GA, Younkin SG, Ashe KH: The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer’s disease. J Neurosci 2002;22:1858–1867.
  17. Unger C, Hedberg MM, Mustafiz T, Svedberg MM, Nordberg A: Early changes in Abeta levels in the brain of APPswe transgenic mice – implication on synaptic density, alpha7 neuronal nicotinic acetylcholine- and N-methyl-D-aspartate receptor levels. Mol Cell Neurosci 2005;30:218–227.
  18. Portelius E, Zhang B, Gustavsson MK, Brinkmalm G, Westman-Brinkmalm A, Zetterberg H, Lee VM, Trojanowski JQ, Blennow K: Effects of gamma-secretase inhibition on the amyloid beta isoform pattern in a mouse model of Alzheimer’s disease. Neurodegener Dis 2009;6:258–262.
  19. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G: Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 1996;274:99–102.
  20. Callahan MJ, Lipinski WJ, Bian F, Durham RA, Pack A, Walker LC: Augmented senile plaque load in aged female beta-amyloid precursor protein-transgenic mice. Am J Pathol 2001;158:1173–1177.
  21. Howlett DR, Richardson JC, Austin A, Parsons AA, Bate ST, Davies DC, Gonzalez MI: Cognitive correlates of Abeta deposition in male and female mice bearing amyloid precursor protein and presenilin-1 mutant transgenes. Brain Res 2004;1017:130–136.
  22. King DL, Arendash GW, Crawford F, Sterk T, Menendez J, Mullan MJ: Progressive and gender-dependent cognitive impairment in the APP(SW) transgenic mouse model for Alzheimer’s disease. Behav Brain Res 1999;103:145–162.
  23. Portelius E, Tran AJ, Andreasson U, Persson R, Brinkmalm G, Zetterberg H, Blennow K, Westman-Brinkmalm A: Characterization of amyloid beta peptides in cerebrospinal fluid by an automated immunoprecipitation procedure followed by mass spectrometry. J Proteome Res 2007;6:4433–4439.
  24. Lambert MP, Velasco PT, Chang L, Viola KL, Fernandez S, Lacor PN, Khuon D, Gong Y, Bigio EH, Shaw P, De Felice FG, Krafft GA, Klein WL: Monoclonal antibodies that target pathological assemblies of Abeta. J Neurochem 2007;100:23–35.
  25. Ikeuchi T, Kaneko H, Miyashita A, Nozaki H, Kasuga K, Tsukie T, Tsuchiya M, Imamura T, Ishizu H, Aoki K, Ishikawa A, Onodera O, Kuwano R, Nishizawa M: Mutational analysis in early-onset familial dementia in the Japanese population. The role of PSEN1 and MAPT R406W mutations. Dement Geriatr Cogn Disord 2008;26:43–49.
  26. Hedberg MM, Svedberg MM, Mustafiz T, Yu WF, Mousavi M, Guan ZZ, Unger C, Nordberg A: Transgenic mice overexpressing human acetylcholinesterase and the Swedish amyloid precursor protein mutation: effect of nicotine treatment. Neuroscience 2008;152:223–233.
  27. Forsberg A, Engler H, Almkvist O, Blomquist G, Hagman G, Wall A, Ringheim A, Langstrom B, Nordberg A: PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiol Aging 2008;29:1456–1465.
  28. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L: Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 2006;5:228–234.
  29. McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, Bush AI, Masters CL: Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann Neurol 1999;46:860–866.
  30. Naslund J, Haroutunian V, Mohs R, Davis KL, Davies P, Greengard P, Buxbaum JD: Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA 2000;283:1571–1577.
  31. Hernandez CM, Kayed R, Zheng H, Sweatt JD, Dineley KT: Loss of alpha7 nicotinic receptors enhances beta-amyloid oligomer accumulation, exacerbating early-stage cognitive decline and septohippocampal pathology in a mouse model of Alzheimer’s disease. J Neurosci 2010;30:2442–2453.
  32. Ballatore C, Lee VM, Trojanowski JQ: Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci 2007;8:663–672.
  33. Guo JP, Arai T, Miklossy J, McGeer PL: Abeta and tau form soluble complexes that may promote self aggregation of both into the insoluble forms observed in Alzheimer’s disease. Proc Natl Acad Sci USA 2006;103:1953–1958.
  34. Terwel D, Muyllaert D, Dewachter I, Borghgraef P, Croes S, Devijver H, Van Leuven F: Amyloid activates GSK-3beta to aggravate neuronal tauopathy in bigenic mice. Am J Pathol 2008;172:786–798.
  35. Liu F, Li B, Tung EJ, Grundke-Iqbal I, Iqbal K, Gong CX: Site-specific effects of tau phosphorylation on its microtubule assembly activity and self-aggregation. Eur J Neurosci 2007;26:3429–3436.
  36. Wang JZ, Grundke-Iqbal I, Iqbal K: Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurosci 2007;25:59–68.
  37. Mattsson N, Savman K, Osterlundh G, Blennow K, Zetterberg H: Converging molecular pathways in human neural development and degeneration. Neurosci Res 2010;66:330–332.
  38. Hughes K, Nikolakaki E, Plyte SE, Totty NF, Woodgett JR: Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. EMBO J 1993;12:803–808.
  39. Plyte SE, Hughes K, Nikolakaki E, Pulverer BJ, Woodgett JR: Glycogen synthase kinase-3: functions in oncogenesis and development. Biochim Biophys Acta 1992;1114:147–162.
  40. Patrick GN, Zhou P, Kwon YT, Howley PM, Tsai LH: p35, the neuronal-specific activator of cyclin-dependent kinase 5 (Cdk5) is degraded by the ubiquitin-proteasome pathway. J Biol Chem 1998;273:24057–24064.
  41. Cruz JC, Tsai LH: Cdk5 deregulation in the pathogenesis of Alzheimer’s disease. Trends Mol Med 2004;10:452–458.


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