nach oben

Erschienen in:

01.06.2009 | Original Paper

Neurofibrillary and neurodegenerative pathology in APP-transgenic mice injected with AAV2-mutant TAU: neuroprotective effects of Cerebrolysin

verfasst von: Kiren Ubhi, Edward Rockenstein, Edith Doppler, Michael Mante, Anthony Adame, Christina Patrick, Margarita Trejo, Leslie Crews, Amy Paulino, Herbert Moessler, Eliezer Masliah

Erschienen in: Acta Neuropathologica | Ausgabe 6/2009

Einloggen, um Zugang zu erhalten

Abstract

Alzheimer’s disease (AD) continues to be the most common cause of cognitive and motor alterations in the aging population. Accumulation of amyloid β (Aβ)-protein oligomers and the microtubule associated protein-TAU might be responsible for the neurological damage. We have previously shown that Cerebrolysin (CBL) reduces the synaptic and behavioral deficits in amyloid precursor protein (APP) transgenic (tg) mice by decreasing APP phosphorylation via modulation of glycogen synthase kinase-3β (GSK3β) and cyclin-dependent kinase-5 (CDK5) activity. These kinases also regulate TAU phosphorylation and are involved in promoting neurofibrillary pathology. In order to investigate the neuroprotective effects of CBL on TAU pathology, a new model for neurofibrillary alterations was developed using somatic gene transfer with adeno-associated virus (AAV2)-mutant (mut) TAU (P301L). The Thy1-APP tg mice (3 m/o) received bilateral injections of AAV2-mutTAU or AAV2-GFP, into the hippocampus. After 3 months, compared to non-tg controls, in APP tg mice intra-hippocampal injections with AAV2-mutTAU resulted in localized increased accumulation of phosphorylated TAU and neurodegeneration. Compared with vehicle controls, treatment with CBL in APP tg injected with AAV2-mutTAU resulted in a significant decrease in the levels of TAU phosphorylation at critical sites dependent on GSK3β and CDK5 activity. This was accompanied by amelioration of the neurodegenerative alterations in the hippocampus. This study supports the concept that the neuroprotective effects of CBL may involve the reduction of TAU phosphorylation by regulating kinase activity.

Nur mit Berechtigung zugänglich

Alvarez XA, Cacabelos R, Laredo M, Couceiro V, Sampedro C, Varela M, Corzo L, Fernandez-Novoa L, Vargas M, Aleixandre M, Linares C, Granizo E, Muresanu D, Moessler H (2006) A 24-week, double-blind, placebo-controlled study of three dosages of Cerebrolysin in patients with mild to moderate Alzheimer’s disease. Eur J Neurol 13:43–54. doi:10.1111/j.1468-1331.2006.01222.x PubMedCrossRef

Andorfer C, Kress Y, Espinoza M, de Silva R, Tucker KL, Barde YA, Duff K, Davies P (2003) Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem 86:582–590. doi:10.1046/j.1471-4159.2003.01879.x PubMedCrossRef

Asuni AA, Boutajangout A, Quartermain D, Sigurdsson EM (2007) Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J Neurosci 27:9115–9129. doi:10.1523/JNEUROSCI.2361-07.2007 PubMedCrossRef

Brion JP, Tremp G, Octave JN (1999) Transgenic expression of the shortest human tau affects its compartmentalization and its phosphorylation as in the pretangle stage of Alzheimer’s disease. Am J Pathol 154:255–270PubMed

Caccamo A, Oddo S, Tran LX, LaFerla FM (2007) Lithium reduces tau phosphorylation but not A beta or working memory deficits in a transgenic model with both plaques and tangles. Am J Pathol 170:1669–1675. doi:10.2353/ajpath.2007.061178 PubMedCrossRef

Chana G, Landau S, Beasley C, Everall IP, Cotter D (2003) Two-dimensional assessment of cytoarchitecture in the anterior cingulate cortex in major depressive disorder, bipolar disorder, and schizophrenia: evidence for decreased neuronal somal size and increased neuronal density. Biol Psychiatry 53:1086–1098. doi:10.1016/S0006-3223(03)00114-8 PubMedCrossRef

Chana G, Everall IP, Crews L, Langford D, Adame A, Grant I, Cherner M, Lazzaretto D, Heaton R, Ellis R, Masliah E (2006) Cognitive deficits and degeneration of interneurons in HIV+ methamphetamine users. Neurology 67:1486–1489. doi:10.1212/01.wnl.0000240066.02404.e6 PubMedCrossRef

Cho JH, Johnson GV (2003) Glycogen synthase kinase 3beta phosphorylates tau at both primed and unprimed sites. Differential impact on microtubule binding. J Biol Chem 278:187–193. doi:10.1074/jbc.M206236200 PubMedCrossRef

Cho JH, Johnson GV (2004) Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3beta (GSK3beta) plays a critical role in regulating tau’s ability to bind and stabilize microtubules. J Neurochem 88:349–358PubMedCrossRef

10.

Davies P, Ghanbari H, Issacs A, Dickson D, Mattiace L, Rosado M, Vincent I (1993) TG3: a better antibody that Alz-50 for the visualization of Alzheimer-type neuronal pathology. Soc Neurosci Abstr 19:1636

11.

DeKosky S, Scheff S (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27:457–464. doi:10.1002/ana.410270502 PubMedCrossRef

12.

Delobel P, Lavenir I, Fraser G, Ingram E, Holzer M, Ghetti B, Spillantini MG, Crowther RA, Goedert M (2008) Analysis of tau phosphorylation and truncation in a mouse model of human tauopathy. Am J Pathol 172:123–131. doi:10.2353/ajpath.2008.070627 PubMedCrossRef

13.

Duff K (2001) Transgenic mouse models of Alzheimer’s disease: phenotype and mechanisms of pathogenesis. Biochem Soc Symp 67:195–202PubMed

14.

Flaherty DB, Soria JP, Tomasiewicz HG, Wood JG (2000) Phosphorylation of human tau protein by microtubule-associated kinases: GSK3beta and cdk5 are key participants. J Neurosci Res 62:463–472. doi:10.1002/1097-4547(20001101)62:3<463::AID-JNR16>3.0.CO;2-7 PubMedCrossRef

15.

Francis-Turner L, Valouskova V (1996) Nerve growth factor and nootropic drug Cerebrolysin but not fibroblast growth factor can reduce spatial memory impairment elicited by fimbria-fornix transection: short-term study. Neurosci Lett 202:1–4. doi:10.1016/0304-3940(95)12240-0 CrossRef

16.

Goedert M, Hasegawa M (1999) The tauopathies: toward an experimental animal model. Am J Pathol 154:1–6PubMed

17.

Gomez-Ramos A, Dominguez J, Zafra D, Corominola H, Gomis R, Guinovart JJ, Avila J (2006) Inhibition of GSK3 dependent tau phosphorylation by metals. Curr Alzheimer Res 3:123–127. doi:10.2174/156720506776383059 PubMedCrossRef

18.

Gotz J, Probst A, Spillantini MG, Schafer T, Jakes R, Burki K, Goedert M (1995) Somatodendritic localization and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform. EMBO J 14:1304–1313PubMed

19.

Gotz J, Chen F, Barmettler R, Nitsch RM (2001) Tau filament formation in transgenic mice expressing P301L tau. J Biol Chem 276:529–534. doi:10.1074/jbc.M006531200 PubMedCrossRef

20.

Gotz J, Chen F, van Dorpe J, Nitsch RM (2001) Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293:1491–1495. doi:10.1126/science.1062097 PubMedCrossRef

21.

Hashimoto M, Sagara Y, Everall IP, Mallory M, Everson A, Langford D, Masliah E (2002) Fibroblast growth factor 1 regulates signaling via the GSK3β pathway: implications for neuroprotection. J Biol Chem 277:32985–32991. doi:10.1074/jbc.M202803200 PubMedCrossRef

22.

Hong M, Chen DC, Klein PS, Lee VM (1997) Lithium reduces tau phosphorylation by inhibition of glycogen synthase kinase-3. J Biol Chem 272:25326–25332. doi:10.1074/jbc.272.40.25326 PubMedCrossRef

23.

Hutton M, Lewis J, Dickson D, Yen S, McGowan E (2001) Analysis of tauopathies with transgenic mice. Trends Mol Med 7:467–470. doi:10.1016/S1471-4914(01)02123-2 PubMedCrossRef

24.

Hyman B, Gomez-Isla T (1994) Alzheimer’s disease is a laminar regional and neural system specific disease, not a global brain disease. Neurobiol Aging 15:353–354. doi:10.1016/0197-4580(94)90031-0 PubMedCrossRef

25.

Hyman BT, Augustinack JC, Ingelsson M (2005) Transcriptional and conformational changes of the tau molecule in Alzheimer’s disease. Biochim Biophys Acta 1739:150–157PubMed

26.

Illenberger S, Zheng-Fischhofer Q, Preuss U, Stamer K, Baumann K, Trinczek B, Biernat J, Godemann R, Mandelkow EM, Mandelkow E (1998) The endogenous and cell cycle-dependent phosphorylation of tau protein in living cells: implications for Alzheimer’s disease. Mol Biol Cell 9:1495–1512PubMed

27.

Jicha GA, Bowser R, Kazam IG, Davies P (1997) Alz-50 and MC-1, a new monoclonal antibody raised to paired helical filaments, recognize conformational epitopes on recombinant tau. J Neurosci Res 48:128–132. doi:10.1002/(SICI)1097-4547(19970415)48:2<128::AID-JNR5>3.0.CO;2-E PubMedCrossRef

28.

Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R (2003) APP processing and synaptic function. Neuron 37:925–937. doi:10.1016/S0896-6273(03)00124-7 PubMedCrossRef

29.

Klein RL, Dayton RD, Leidenheimer NJ, Jansen K, Golde TE, Zweig RM (2006) Efficient neuronal gene transfer with AAV8 leads to neurotoxic levels of tau or green fluorescent proteins. Mol Ther 13:517–527. doi:10.1016/j.ymthe.2005.10.008 PubMedCrossRef

30.

Koo E, Lansbury PJ, Kelly J (1999) Amyloid diseases: abnormal protein aggregation in neurodegeneration. Proc Natl Acad Sci USA 96:9989–9990. doi:10.1073/pnas.96.18.9989 PubMedCrossRef

31.

Lee HG, Perry G, Moreira PI, Garrett MR, Liu Q, Zhu X, Takeda A, Nunomura A, Smith MA (2005) Tau phosphorylation in Alzheimer’s disease: pathogen or protector? Trends Mol Med 11:164–169. doi:10.1016/j.molmed.2005.02.008 PubMedCrossRef

32.

Lee VM (1996) Regulation of tau phosphorylation in Alzheimer’s disease. Ann N Y Acad Sci 777:107–113. doi:10.1111/j.1749-6632.1996.tb34408.x PubMedCrossRef

33.

Lee VM, Trojanowski JQ (1999) Neurodegenerative tauopathies: human disease and transgenic mouse models. Neuron 24:507–510. doi:10.1016/S0896-6273(00)81106-X PubMedCrossRef

34.

Lee VM, Goedert M, Trojanowski JQ (2001) Neurodegenerative tauopathies. Annu Rev Neurosci 24:1121–1159. doi:10.1146/annurev.neuro.24.1.1121 PubMedCrossRef

35.

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. doi:10.1126/science.1058189 PubMedCrossRef

36.

Li T, Hawkes C, Qureshi HY, Kar S, Paudel HK (2006) Cyclin-dependent protein kinase 5 primes microtubule-associated protein tau site-specifically for glycogen synthase kinase 3beta. Biochemistry 45:3134–3145. doi:10.1021/bi051635j PubMedCrossRef

37.

Li T, Paudel HK (2006) Glycogen synthase kinase 3beta phosphorylates Alzheimer’s disease-specific Ser396 of microtubule-associated protein tau by a sequential mechanism. Biochemistry 45:3125–3133. doi:10.1021/bi051634r PubMedCrossRef

38.

Mallory M, Honer W, Hsu L, Johnson R, Masliah E (1999) In vitro synaptotrophic effects of Cerebrolysin in NT2N cells. Acta Neuropathol 97:437–446. doi:10.1007/s004010051012 PubMedCrossRef

39.

Mandelkow EM, Biernat J, Drewes G, Gustke N, Trinczek B, Mandelkow E (1995) Tau domains, phosphorylation, and interactions with microtubules. Neurobiol Aging 16:355–362. doi:10.1016/0197-4580(95)00025-A discussion 362–353PubMedCrossRef

40.

Mandelkow EM, Schweers O, Drewes G, Biernat J, Gustke N, Trinczek B, Mandelkow E (1996) Structure, microtubule interactions, and phosphorylation of tau protein. Ann N Y Acad Sci 777:96–106. doi:10.1111/j.1749-6632.1996.tb34407.x PubMedCrossRef

41.

Masliah E (1995) Mechanisms of synaptic dysfunction in Alzheimer’s disease. Histol Histopathol 10:509–519PubMed

42.

Masliah E, Armasolo F, Veinbergs I, Mallory M, Samuel W (1999) Cerebrolysin ameliorates performance deficits and neuronal damage in apolipoprotein E-deficient mice. Pharmacol Biochem Behav 62:239–245PubMedCrossRef

43.

Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L (2000) Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 287:1265–1269. doi:10.1126/science.287.5456.1265 PubMedCrossRef

44.

McCown TJ (2005) Adeno-associated virus (AAV) vectors in the CNS. Curr Gene Ther 5:333–338. doi:10.2174/1566523054064995 PubMedCrossRef

45.

Mi K, Johnson GV (2006) The role of tau phosphorylation in the pathogenesis of Alzheimer’s disease. Curr Alzheimer Res 3:449–463. doi:10.2174/156720506779025279 PubMedCrossRef

46.

Michel G, Mercken M, Murayama M, Noguchi K, Ishiguro K, Imahori K, Takashima A (1998) Characterization of tau phosphorylation in glycogen synthase kinase-3beta and cyclin dependent kinase-5 activator (p23) transfected cells. Biochim Biophys Acta 1380:177–182PubMed

47.

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 20:4050–4058PubMed

48.

Noble W, Planel E, Zehr C, Olm V, Meyerson J, Suleman F, Gaynor K, Wang L, LaFrancois J, Feinstein B, Burns M, Krishnamurthy P, Wen Y, Bhat R, Lewis J, Dickson D, Duff K (2005) Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci USA 102:6990–6995. doi:10.1073/pnas.0500466102 PubMedCrossRef

49.

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. doi:10.1016/S0896-6273(03)00434-3 PubMedCrossRef

50.

Oddo S, Billings L, Kesslak JP, Cribbs DH, LaFerla FM (2004) Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 43:321–332. doi:10.1016/j.neuron.2004.07.003 PubMedCrossRef

51.

Oddo S, Vasilevko V, Caccamo A, Kitazawa M, Cribbs DH, LaFerla FM (2006) Reduction of soluble Abeta and tau, but not soluble Abeta alone, ameliorates cognitive decline in transgenic mice with plaques and tangles. J Biol Chem 281:39413–39423. doi:10.1074/jbc.M608485200 PubMedCrossRef

52.

Paxinos G, Franklin K (2003) The mouse brain in stereotaxic coordinates. Academic Press, NY

53.

Peel AL, Klein RL (2000) Adeno-associated virus vectors: activity and applications in the CNS. J Neurosci Methods 98:95–104. doi:10.1016/S0165-0270(00)00183-7 PubMedCrossRef

54.

Perez M, Hernandez F, Lim F, Diaz-Nido J, Avila J (2003) Chronic lithium treatment decreases mutant tau protein aggregation in a transgenic mouse model. J Alzheimers Dis 5:301–308PubMed

55.

Perez M, Ribe E, Rubio A, Lim F, Moran MA, Ramos PG, Ferrer I, Isla MT, Avila J (2005) Characterization of a double (amyloid precursor protein-tau) transgenic: tau phosphorylation and aggregation. Neuroscience 130:339–347. doi:10.1016/j.neuroscience.2004.09.029 PubMedCrossRef

56.

Poorkaj P, Grossman M, Steinbart E, Payami H, Sadovnick A, Nochlin D, Tabira T, Trojanowski JQ, Borson S, Galasko D, Reich S, Quinn B, Schellenberg G, Bird TD (2001) Frequency of tau gene mutations in familial and sporadic cases of non-Alzheimer dementia. Arch Neurol 58:383–387. doi:10.1001/archneur.58.3.383 PubMedCrossRef

57.

Reynolds CH, Betts JC, Blackstock WP, Nebreda AR, Anderton BH (2000) Phosphorylation sites on tau identified by nanoelectrospray mass spectrometry: differences in vitro between the mitogen-activated protein kinases ERK2, c-Jun N-terminal kinase and P38, and glycogen synthase kinase-3beta. J Neurochem 74:1587–1595. doi:10.1046/j.1471-4159.2000.0741587.x PubMedCrossRef

58.

Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, Yu GQ, Mucke L (2007) Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science 316:750–754. doi:10.1126/science.1141736 PubMedCrossRef

59.

Rockenstein E, McConlogue L, Tan H, Power M, Masliah E, Mucke L (1995) Levels and alternative splicing of amyloid β protein precursor (APP) transcripts in brains of APP transgenic mice and humans with Alzheimer’s disease. J Biol Chem 270:28257–28267. doi:10.1074/jbc.270.47.28257 PubMedCrossRef

60.

Rockenstein E, Mallory M, Mante M, Sisk A, Masliah E (2001) Early formation of mature amyloid-b proteins deposits in a mutant APP transgenic model depends on levels of Ab1–42. J Neurosci Res 66:573–582. doi:10.1002/jnr.1247 PubMedCrossRef

61.

Rockenstein E, Mallory M, Mante M, Alford M, Windisch M, Moessler H, Masliah E (2002) Effects of Cerebrolysin on amyloid-beta deposition in a transgenic model of Alzheimer’s disease. J Neural Transm Suppl 62:327–336PubMed

62.

Rockenstein E, Adame A, Mante M, Moessler H, Windisch M, Masliah E (2003) The neuroprotective effects of Cerebrolysin trade mark in a transgenic model of Alzheimer’s disease are associated with improved behavioral performance. J Neural Transm 110:1313–1327. doi:10.1007/s00702-003-0025-7 PubMedCrossRef

63.

Rockenstein E, Adame A, Mante M, Larrea G, Crews L, Windisch M, Moessler H, Masliah E (2005) Amelioration of the cerebrovascular amyloidosis in a transgenic model of Alzheimer’s disease with the neurotrophic compound cerebrolysin. J Neural Transm 112:269–282. doi:10.1007/s00702-004-0181-4 PubMedCrossRef

64.

Rockenstein E, Torrance M, Mante M, Adame A, Paulino A, Rose JB, Crews L, Moessler H, Masliah E (2006) Cerebrolysin decreases amyloid-beta production by regulating amyloid protein precursor maturation in a transgenic model of Alzheimer’s disease. J Neurosci Res 83(7):1252–1261PubMedCrossRef

65.

66.

Rockenstein E, Mante M, Adame A, Crews L, Moessler H, Masliah E (2007) Effects of Cerebrolysin trade mark on neurogenesis in an APP transgenic model of Alzheimer’s disease. Acta Neuropathol 113:265–275. doi:10.1007/s00401-006-0166-5 PubMedCrossRef

67.

Rockenstein E, Torrance M, Adame A, Mante M, Bar-on P, Rose JB, Crews L, Masliah E (2007) Neuroprotective effects of regulators of the glycogen synthase kinase-3beta signaling pathway in a transgenic model of Alzheimer’s disease are associated with reduced amyloid precursor protein phosphorylation. J Neurosci 27:1981–1991. doi:10.1523/JNEUROSCI.4321-06.2007 PubMedCrossRef

68.

Ruther E, Ritter R, Apecechea M, Freitag S, Windisch M (1994) Efficacy of Cerebrolysin in Alzheimer’s disease. In: Jellinger K, Ladurner G, Windisch M (eds) New trends in the diagnosis and therapy of Alzheimer’s disease. Springer, Vienna, pp 131–141

69.

Ruther E, Ritter R, Apecechea M, Freytag S, Windisch M (1994) Efficacy of the peptidergic nootropic drug cerebrolysin in patients with senile dementia of the Alzheimer’s type (SDAT). Pharmacopsychiatry 27:32–40. doi:10.1055/s-2007-1014271 PubMedCrossRef

70.

Ryder J, Su Y, Liu F, Li B, Zhou Y, Ni B (2003) Divergent roles of GSK3 and CDK5 in APP processing. Biochem Biophys Res Commun 312:922–929. doi:10.1016/j.bbrc.2003.11.014 PubMedCrossRef

71.

Schubert D, Heinemann S, Carlisle W, Tarikas H, Kimes B, Patrick J, Steinbach JH, Culp W, Brandt BL (1974) Clonal cell lines from the rat central nervous system. Nature 249:224–227. doi:10.1038/249224a0 PubMedCrossRef

72.

Selenica ML, Jensen HS, Larsen AK, Pedersen ML, Helboe L, Leist M, Lotharius J (2007) Efficacy of small-molecule glycogen synthase kinase-3 inhibitors in the postnatal rat model of tau hyperphosphorylation. Br J Pharmacol 152:959–979. doi:10.1038/sj.bjp.0707471 PubMedCrossRef

73.

Selkoe DJ, Schenk D (2003) Alzheimer’s disease: molecular understanding predicts amyloid-based therapeutics. Annu Rev Pharmacol Toxicol 43:545–584. doi:10.1146/annurev.pharmtox.43.100901.140248 PubMedCrossRef

74.

Selkoe DJ (2008) Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res 192:106–113. doi:10.1016/j.bbr.2008.02.016 PubMedCrossRef

75.

Sigurdsson EM (2008) Immunotherapy targeting pathological tau protein in Alzheimer’s disease and related tauopathies. J Alzheimers Dis 15:157–168PubMed

76.

Sinha S, Anderson J, John V, McConlogue L, Basi G, Thorsett E, Schenk D (2000) Recent advances in the understanding of the processing of APP to beta amyloid peptide. Ann N Y Acad Sci 920:206–208PubMedCrossRef

77.

Spencer B, Rockenstein E, Crews L, Marr R, Masliah E (2007) Novel strategies for Alzheimer’s disease treatment. Expert Opin Biol Ther 7:1853–1867. doi:10.1517/14712598.7.12.1853 PubMedCrossRef

78.

Takahashi M, Yasutake K, Tomizawa K (1999) Lithium inhibits neurite growth and tau protein kinase I/glycogen synthase kinase-3beta-dependent phosphorylation of juvenile tau in cultured hippocampal neurons. J Neurochem 73:2073–2083PubMed

79.

Takashima A (2006) GSK-3 is essential in the pathogenesis of Alzheimer’s disease. J Alzheimers Dis 9:309–317PubMed

80.

Tatebayashi Y, Lee MH, Li L, Iqbal K, Grundke-Iqbal I (2003) The dentate gyrus neurogenesis: a therapeutic target for Alzheimer’s disease. Acta Neuropathol 105:225–232PubMed

81.

Terry R, Hansen L, Masliah E (1994) Structural basis of the cognitive alterations in Alzheimer disease. In: Terry R, Katzman R (eds) Alzheimer disease. Raven Press, New York, pp 179–196

82.

Trojanowski J, Schmidt M, Shin R-W, Bramblett G, Rao D, Lee V-Y (1993) Altered Tau and neurofilament proteins in neurodegenerative diseases: diagnostic implications for Alzheimer’s disease and Lewy body dementias. Brain Pathol 3:45–54. doi:10.1111/j.1750-3639.1993.tb00725.x PubMedCrossRef

83.

Trojanowski JQ, Lee VM (1994) Phosphorylation of neuronal cytoskeletal proteins in Alzheimer’s disease and Lewy body dementias. Ann N Y Acad Sci 747:92–109PubMedCrossRef

84.

Veinbergs I, Mante M, Mallory M, Masliah E (2000) Neurotrophic effects of Cerebrolysin in animal models of excitotoxicity. J Neural Transm Suppl 59:273–280PubMed

85.

Walsh DM, Selkoe DJ (2007) A beta oligomers—a decade of discovery. J Neurochem 101:1172–1184. doi:10.1111/j.1471-4159.2006.04426.x PubMedCrossRef

86.

Weaver CL, Espinoza M, Kress Y, Davies P (2000) Conformational change as one of the earliest alterations of tau in Alzheimer’s disease. Neurobiol Aging 21:719–727. doi:10.1016/S0197-4580(00)00157-3 PubMedCrossRef

87.

Wei ZH, He QB, Wang H, Su BH, Chen HZ (2007) Meta-analysis: the efficacy of nootropic agent Cerebrolysin in the treatment of Alzheimer’s disease. J Neural Transm 114:629–634. doi:10.1007/s00702-007-0630-y PubMedCrossRef

88.

Wen Y, Yang SH, Liu R, Perez EJ, Brun-Zinkernagel AM, Koulen P, Simpkins JW (2007) Cdk5 is involved in NFT-like tauopathy induced by transient cerebral ischemia in female rats. Biochim Biophys Acta 1772:473–483PubMed

89.

Woods YL, Cohen P, Becker W, Jakes R, Goedert M, Wang X, Proud CG (2001) The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2Bepsilon at Ser539 and the microtubule-associated protein tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase. Biochem J 355:609–615PubMed

Titel: Neurofibrillary and neurodegenerative pathology in APP-transgenic mice injected with AAV2-mutant TAU: neuroprotective effects of Cerebrolysin
verfasst von: Kiren Ubhi
Edward Rockenstein
Edith Doppler
Michael Mante
Anthony Adame
Christina Patrick
Margarita Trejo
Leslie Crews
Amy Paulino
Herbert Moessler
Eliezer Masliah
Publikationsdatum: 01.06.2009
Verlag: Springer-Verlag
Erschienen in: Acta Neuropathologica / Ausgabe 6/2009
Print ISSN: 0001-6322
Elektronische ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-009-0505-4

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Neurologie

23.04.2024 | Demenz | Nachrichten

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Neurofibrillary and neurodegenerative pathology in APP-transgenic mice injected with AAV2-mutant TAU: neuroprotective effects of Cerebrolysin

Abstract

Leitlinien kompakt für die Neurologie

Neu im Fachgebiet Neurologie

Demenzkranke durch Antipsychotika vielfach gefährdet

Parkinson-Therapie im Wandel – aktuelle Leitlinie im Fokus

Auf diese Krankheiten bei Geflüchteten sollten Sie vorbereitet sein

Hustenstiller lindert Agitation bei Alzheimer

Update Neurologie

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 6/2009

APP/PS1KI bigenic mice develop early synaptic deficits and hippocampus atrophy

Hippocampal sclerosis with four-repeat tau-positive round inclusions in the dentate gyrus: a new type of four-repeat tauopathy

Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction

Expression of EAAT-1 distinguishes choroid plexus tumors from normal and reactive choroid plexus epithelium

Histopathologic predictors of pilocytic astrocytoma event-free survival

Truncated tau at D421 is associated with neurodegeneration and tangle formation in the brain of Alzheimer transgenic models

Leitlinien kompakt für die Neurologie

Neu im Fachgebiet Neurologie

Demenzkranke durch Antipsychotika vielfach gefährdet

Parkinson-Therapie im Wandel – aktuelle Leitlinie im Fokus

Auf diese Krankheiten bei Geflüchteten sollten Sie vorbereitet sein

Hustenstiller lindert Agitation bei Alzheimer

Update Neurologie