Journal Mobile Options
Table of Contents
Vol. 4, No. 5, 2007
Issue release date: July 2007
Neurodegenerative Dis 2007;4:349–365
(DOI:10.1159/000105156)

Current Insights into Molecular Mechanisms of Alzheimer Disease and Their Implications for Therapeutic Approaches

Van Broeck B. · Van Broeckhoven C. · Kumar-Singh S.
To view the fulltext, log in and/or choose pay-per-view option

Individual Users: Register with Karger Login Information

Please create your User ID & Password





Contact Information











I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in

Abstract

During the last 10 years, a lot of progress has been made in unraveling the pathogenic cascade leading to Alzheimer disease (AD). According to the most widely accepted hypothesis, production and aggregation of the amyloid β (Aβ) peptide plays a key role in AD, and thus therapeutic interference with these processes is the subject of intense research. However, some important aspects of the disease mechanism are not yet fully understood. There is no consensus as yet on whether the disease acts through a loss- (LOF) or a gain-of-function (GOF) mechanism. While for many years, an increased production of Aβ42 was considered to be the prime culprit for the initiation of the disease process, and accordingly Aβ42 is elevated by AD-related presenilin(PS) mutations, recent data strongly suggest that PS mutations also lead to a LOF of PS towards a plethora of its substrates including amyloid precursor protein. How this PS LOF, especially decreased Aβ40 secretion due to mutant PS, impacts on the disease pathogenesis is yet to be elucidated. Secondly, vascular abnormalities – frequently observed to co-occur with AD – might also play a critical role in the initiation and aggravation of AD pathology given that the elimination of Aβ through a vascular route is an important brain Aβ clearance mechanism and its failure leads to formation of vascular amyloidosis and dense-core plaques. In this review, we will first focus on the important issue of a LOF versus a GOF mechanism for AD due to mutant PS, as well as on the possible role of vascular damage and reduced perfusion in AD. Special emphasis will be given to some of the AD mouse models that have helped to gain insights into the disease mechanism. Secondly, considering these mechanistic insights, we will discuss some therapeutic strategies which are currently in clinical or preclinical trials for AD.



Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Selkoe DJ: Cell biology of protein misfolding: the examples of Alzheimer’s and Parkinson’s diseases. Nat Cell Biol 2004;6:1054–1061.
  2. Suzuki N, Cheung TT, Cai XD, Odaka A, Otvos L, Eckman C, Golde TE, Younkin SG: An increased percentage of long amyloid βprotein secreted by familial amyloid βprotein precursor (β APP717) mutants. Science 1994;264:1336–1340.
  3. Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, Prada CM, Kim G, Seekins S, Yager D, Slunt HH, Wang R, Seeger M, Levey AI, Gandy SE, Copeland NG, Jenkins NA, Price DL, Younkin SG, Sisodia SS: Familial Alzheimer’s disease-linked presenilin 1 variants elevate Aβ1–42/1–40 ratio in vitro and in vivo. Neuron 1996;17:1005–1013.
  4. Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y: Visualization of Aβ 42(43) and Aβ 40 in senile plaques with end-specific Aβ monoclonals: evidence that an initially deposited species is Aβ 42(43). Neuron 1994;13:45–53.
  5. De Strooper B: Aph-1, Pen-2, and nicastrin with presenilin generate an active γ-secretase complex. Neuron 2003;38:9–12.
  6. Chen F, Hasegawa H, Schmitt-Ulms G, Kawarai T, Bohm C, Katayama T, Gu Y, Sanjo N, Glista M, Rogaeva E, Wakutani Y, Pardossi-Piquard R, Ruan X, Tandon A, Checler F, Marambaud P, Hansen K, Westaway D, George-Hyslop P, Fraser P: TMP21 is a presenilin complex component that modulates γ-secretase but not ε-secretase activity. Nature 2006;440:1208–1212.
  7. Zhao G, Mao G, Tan J, Dong Y, Cui MZ, Kim SH, Xu X: Identification of a new presenilin-dependent ζ-cleavage site within the transmembrane domain of amyloid precursor protein. J Biol Chem 2004;279:50647–50650.
  8. Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, wClemens J, Donaldson T, Gillespie F, et al: Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 1995;373:523–527.
  9. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G: Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 1996;274:99–102.
  10. 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: Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1. Nature 1996;383:710–713.
  11. Borchelt DR, Ratovitski T, van Are J, Lee MK, Gonzales V, Jenkins NA, Copeland NG, Price DL, Sisodia SS: Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 1997;19:939–945.
  12. 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: Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 1998;4:97–100.
  13. Perez-Tur J, Froelich S, Prihar G, Crook R, Baker M, Duff K, Wragg M, Busfield F, Lendon C, Clark RF, Roques P, Fuldner RA, Johnston J, Cowburn R, Forsell C, Axelman K, Lilius L, Houlden H, Karran E, Roberts GW, Rossor M, Adams MD, Hardy J, Goate A: A mutation in Alzheimer’s disease destroying a splice acceptor site in the presenilin-1 gene. Neuroreport 1995;7:297–301.
  14. Qian S, Jiang P, Guan XM, Singh G, Trumbauer ME, Yu H, Chen HY, Van de Ploeg LH, Zheng H: Mutant human presenilin 1 protects presenilin 1 null mouse against embryonic lethality and elevates Aβ1–42/43 expression. Neuron 1998;20:611–617.
  15. Wang R, Wang B, He W, Zheng H: Wild-type presenilin 1 protects against Alzheimer’s disease mutation-induced amyloid pathology. J Biol Chem 2006;281:15330–15336.
  16. Bentahir M, Nyabi O, Verhamme J, Tolia A, Horre K, Wiltfang J, Esselmann H, De Strooper B: Presenilin clinical mutations can affect γ-secretase activity by different mechanisms. J Neurochem 2006;96:732–742.
  17. Kumar-Singh S, Theuns J, Van Broeck B, Pirici D, Vennekens K, Corsmit E, Cruts M, Dermaut B, Wang R, Van Broeckhoven C: Mean age-of-onset of familial Alzheimer disease caused by presenilin mutations correlates with both increased Aβ42 and decreased Aβ40. Hum Mutat 2006;27:686–695.
  18. Davis JA, Naruse S, Chen H, Eckman C, Younkin S, Price DL, Borchelt DR, Sisodia SS, Wong PC: An Alzheimer’s disease-linked PS1 variant rescues the developmental abnormalities of PS1-deficient embryos. Neuron 1998;20:603–609.
  19. Baumeister R, Leimer U, Zweckbronner I, Jakubek C, Grunberg J, Haass C: Human presenilin-1, but not familial Alzheimer’s disease (FAD) mutants, facilitate Caenorhabditis elegans Notch signalling independently of proteolytic processing. Genes Funct 1997;1:149–159.
  20. Levitan D, Doyle TG, Brousseau D, Lee MK, Thinakaran G, Slunt HH, Sisodia SS, Greenwald I: Assessment of normal and mutant human presenilin function in Caenorhabditis elegans. Proc Natl Acad Sci USA 1996;93:14940–14944.
  21. Rovelet-Lecrux A, Hannequin D, Raux G, Meur NL, Laquerriere A, Vital A, Dumanchin C, Feuillette S, Brice A, Vercelletto M, Dubas F, Frebourg T, Campion D: APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet 2006;38:24–26.
  22. Sleegers K, Brouwers N, Gijselinck I, Theuns J, Goossens D, Wauters J, Del Favero J, Cruts M, van Duijn CM, Van Broeckhoven C: APP duplication is sufficient to cause early onset Alzheimer’s dementia with cerebral amyloid angiopathy. Brain 2006;129:2977–2983.
  23. Theuns J, Brouwers N, Engelborghs S, Sleegers K, Bogaerts V, Corsmit E, De Pooter T, van Duijn CM, De Deyn PP, Van Broeckhoven C: Promoter mutations that increase amyloid precursor-protein expression are associated with Alzheimer disease. Am J Hum Genet 2006;78:936–946.
  24. Brouwers N, Sleegers K, Engelborghs S, Bogaerts V, Serneels S, Kamali K, Corsmit E, De Leenheir E, Martin JJ, De Deyn PP, Van Broeckhoven C, Theuns J: Genetic risk and transcriptional variability of amyloid precursor protein in Alzheimer’s disease. Brain 2006;129:2984–2991.
  25. Ancolio K, Dumanchin C, Barelli H, Warter JM, Brice A, Campion D, Frebourg T, Checler F: Unusual phenotypic alteration of β amyloid precursor protein (APP) maturation by a new Val-715 → Met APP-770 mutation responsible for probable early-onset Alzheimer’s disease. Proc Natl Acad Sci USA 1999;96:4119–4124.
  26. Kumar-Singh S, De Jonghe C, Cruts M, Kleinert R, Wang R, Mercken M, De Strooper B, Vanderstichele H, Lofgren A, Vanderhoeven I, Backhovens H, Vanmechelen E, Kroisel PM, Van Broeckhoven C: Nonfibrillar diffuse amyloid deposition due to a γ(42)-secretase site mutation points to an essential role for N-truncated Aβ(42) in Alzheimer’s disease. Hum Mol Genet 2000;9:2589–2598.
  27. De Jonghe C, Esselens C, Kumar-Singh S, Craessaerts K, Serneels S, Checler F, Annaert W, Van Broeckhoven C, De Strooper B: Pathogenic APP mutations near the γ-secretase cleavage site differentially affect Aβ secretion and APP C-terminal fragment stability. Hum Mol Genet 2001;10:1665–1671.
  28. Gouras GK, Almeida CG, Takahashi RH: Intraneuronal Aβ accumulation and origin of plaques in Alzheimer’s disease. Neurobiol Aging 2005;26:1235–1244.
  29. Van Broeck B, Vanhoutte G, Pirici D, Van Dam D, Wils H, Cuijt.I, Vennekens K, Zabielski M, Theuns J, De Deyn P, Van der Linden A, Van Broeckhoven C, Kumar-Singh S: Intraneuronal amyloid-β and reduced brain volume in a novel APP T714I mouse model for Alzheimer’s disease. Neurobiol Aging 2006, E-pub ahead of print.
  30. Deng Y, Tarassishin L, Kallhoff V, Peethumnongsin E, Wu L, Li YM, Zheng H: Deletion of presenilin 1 hydrophilic loop sequence leads to impaired γ-secretase activity and exacerbated amyloid pathology. J Neurosci 2006;26:3845–3854.
  31. McGowan E, Pickford F, Kim J, Onstead L, Eriksen J, Yu C, Skipper L, Murphy MP, Beard J, Das P, Jansen K, Delucia M, Lin WL, Dolios G, Wang R, Eckman CB, Dickson DW, Hutton M, Hardy J, Golde T: Aβ42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron 2005;47:191–199.
  32. Kim J, Onstead L, Randle S, Price R, Smithson L, Zwizinski C, Dickson DW, Golde T, McGowan E: Abeta40 inhibits amyloid deposition in vivo. J Neurosci 2007;27:627–633.
  33. Kumar-Singh S, Julliams A, Nuyens D, Labeur C, Vennekens K, Serneels S, Van Osta P, Geerts H, De Strooper B, Van Broeckhoven C: In vitro studies of Flemish, Dutch, and wild type amyloid β (Aβ) provide evidence for a two-stage Aβ neurotoxicity. Neurobiol Dis 2002;11:300–310.

    External Resources

  34. Kumar-Singh S, Cras P, Wang R, Kros JM, van Swieten J, Lubke U, Ceuterick C, Serneels S, Vennekens K, Timmermans J-P, Van Marck E, Martin J-J, van Duijn C, Van Broeckhoven C: Dense-core senile plaques in the Flemish variant of Alzheimer’s disease are vasocentric. Am J Pathol 2002;161:507–520.
  35. Van Broeckhoven C, Kumar-Singh S: Genetics and pathology of α-secretase site AβPP mutations in the understanding of Alzheimer’s disease. J Alzheimers Dis 2006;9:389–398.
  36. Chen F, Gu Y, Hasegawa H, Ruan X, Arawaka S, Fraser P, Westaway D, Mount H, George-Hyslop P: Presenilin 1 mutations activate γ 42-secretase but reciprocally inhibit ε-secretase cleavage of amyloid precursor protein (APP) and S3-cleavage of notch. J Biol Chem 2002;277:36521–36526.
  37. Kulic L, Walter J, Multhaup G, Teplow DB, Baumeister R, Romig H, Capell A, Steiner H, Haass C: Separation of presenilin function in amyloid β-peptide generation and endoproteolysis of Notch. Proc Natl Acad Sci USA 2000;97:5913–5918.
  38. Saura CA, Choi SY, Beglopoulos V, Malkani S, Zhang D, Shankaranarayana Rao BS, Chattarji S, Kelleher RJ III, Kandel ER, Duff K, Kirkwood A, Shen J: Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron 2004;42:23–36.
  39. Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S: Skeletal and CNS defects in presenilin-1-deficient mice. Cell 1997;89:629–639.
  40. Mitsuda N, Ohkubo N, Tamatani M, Lee YD, Taniguchi M, Namikawa K, Kiyama H, Yamaguchi A, Sato N, Sakata K, Ogihara T, Vitek MP, Tohyama M: Activated cAMP-response element-binding protein regulates neuronal expression of presenilin-1. J Biol Chem 2001;276:9688–9698.
  41. Theuns J, Remacle J, Killick R, Corsmit E, Vennekens K, Huylebroeck D, Cruts M, Van Broeckhoven C: Alzheimer-associated C allele of the promoter polymorphism –22C → T causes a critical neuron-specific decrease of presenilin 1 expression. Hum Mol Genet 2003;12:869–877.
  42. Baki L, Shioi J, Wen P, Shao Z, Schwarzman A, Gama-Sosa M, Neve R, Robakis NK: PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: effects of FAD mutations. EMBO J 2004;23:2586–2596.
  43. Song W, Nadeau P, Yuan M, Yang X, Shen J, Yankner BA: Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations. Proc Natl Acad Sci USA 1999;96:6959–6963.
  44. Marambaud P, Wen PH, Dutt A, Shioi J, Takashima A, Siman R, Robakis NK: A CBP binding transcriptional repressor produced by the PS1/ε-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell 2003;114:635–645.
  45. Georgakopoulos A, Litterst C, Ghersi E, Baki L, Xu C, Serban G, Robakis NK: Metalloproteinase/presenilin1 processing of ephrinB regulates EphB-induced Src phosphorylation and signaling. EMBO J 2006;25:1242–1252.
  46. Moehlmann T, Winkler E, Xia X, Edbauer D, Murrell J, Capell A, Kaether C, Zheng H, Ghetti B, Haass C, Steiner H: Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Aβ 42 production. Proc Natl Acad Sci USA 2002;99:8025–8030.
  47. Wiley JC, Hudson M, Kanning KC, Schecterson LC, Bothwell M: Familial Alzheimer’s disease mutations inhibit γ-secretase-mediated liberation of β-amyloid precursor protein carboxy-terminal fragment. J Neurochem 2005;94:1189–1201.
  48. Walker ES, Martinez M, Brunkan AL, Goate A: Presenilin 2 familial Alzheimer’s disease mutations result in partial loss of function and dramatic changes in Aβ 42/40 ratios. J Neurochem 2005;92:294–301.
  49. Dermaut B, Kumar-Singh S, Engelborghs S, Theuns J, Rademakers R, Sacrens J, Pickut BA, Peeters K, Van den Broeck M, Vennekens K, Claes S, Cruts M, Cras P, Martin JJ, Van Broeckhoven C, De Deyn PP: A novel presenilin 1 mutation associated with Pick’s disease but not β-amyloid plaques. Ann Neurol 2004;55:617–626.
  50. Rogaeva E, Fafel K, Song Y, Medeiros B, Sato C, Liang Y, Richard E, Rogaev E, Frommelt P, Sadovnick AD, Meschino W, Rockwood K, Boss M, Mayeux R, St George-Hyslop P: Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology 2001;57:621–625.
  51. Boeve BF, Baker M, Dickson DW, Parisi JE, Giannini C, Josephs KA, Hutton M, Pickering-Brown SM, Rademakers R, Tang-Wai D, Jack CR Jr, Kantarci K, Shiung MM, Golde T, Smith GE, Geda YE, Knopman DS, Petersen RC: Frontotemporal dementia and parkinsonism associated with the IVS1 + 1G → A mutation in progranulin: a clinicopathologic study. Brain 2006;129:3103–3114.
  52. Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M: Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 2006;442:916–919.
  53. Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, Rademakers R, Vandenberghe R, Dermaut B, Martin JJ, van Duijn C, Peeters K, Sciot R, Santens P, De Pooter T, Mattheijssens M, Van den Broeck M, Cuijt I, Vennekens K, De Deyn PP, Kumar-Singh S, Van Broeckhoven C: Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 2006;442:920–924.
  54. Raux G, Gantier R, Thomas-Anterion C, Boulliat J, Verpillat P, Hannequin D, Brice A, Frebourg T, Campion D: Dementia with prominent frontotemporal features associated with L113P presenilin 1 mutation. Neurology 2000;55:1577–1578.
  55. Farkas E, Luiten PGM: Cerebral microvascular pathology in aging and Alzheimer’s disease. Prog Neurobiol 2001;64:575–611.
  56. Kumar-Singh S, Pirici D, McGowan E, Serneels S, Ceuterick C, Hardy J, Duff K, Dickson D, Van Broeckhoven C: Dense core plaques in Tg2576 and PSAPP mouse models of Alzheimer’s disease are centered on vessel walls. Am J Pathol 2005;167:527–543.
  57. Herzig MC, Winkler DT, Burgermeister P, Pfeifer M, Kohler E, Schmidt SD, Danner S, Abramowski D, Sturchler-Pierrat C, Burki K, van Duinen SG, Maat-Schieman MLC, Staufenbiel M, Mathews PM, Jucker M: A β is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat Neurosci 2004;7:954–960.
  58. Pappas BA, de la Torre JC, Davidson CM, Keyes MT, Fortin T: Chronic reduction of cerebral blood flow in the adult rat: late-emerging CA1 cell loss and memory dysfunction. Brain Res 1996;708:50–58.
  59. Oosthuyse B, Moons L, Storkebaum E, Beck H, Nuyens D, Brusselmans K, Van Dorpe J, Hellings P, Gorselink M, Heymans S, Theilmeier G, Dewerchin M, Laudenbach V, Vermylen P, Raat H, Acker T, Vleminckx V, Van Den Bosch L, Cashman N, Fujisawa H, Drost MR, Sciot R, Bruyninckx F, Hicklin DJ, Ince C, Gressens P, Lupu F, Plate KH, Robberecht W, Herbert JM, Collen D, Carmeliet P: Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet 2001;28:131–138.
  60. Comery TA, Martone RL, Aschmies S, Atchison KP, Diamantidis G, Gong X, Zhou H, Kreft AF, Pangalos MN, Sonnenberg-Reines J, Jacobsen JS, Marquis KL: Acute γ-secretase inhibition improves contextual fear conditioning in the Tg2576 mouse model of Alzheimer’s disease. J Neurosci 2005;25:8898–8902.
  61. Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T, Engstrom L, Pinzon-Ortiz M, Fine JS, Lee HJ, Zhang L, Higgins GA, Parker EM: Chronic treatment with the γ-secretase inhibitor LY-411,575 inhibits β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 2004;279:12876–12882.
  62. Roberds SL, Anderson J, Basi G, Bienkowski MJ, Branstetter DG, Chen KS, Freedman SB, Frigon NL, Games D, Hu K, Johnson-Wood K, Kappenman KE, Kawabe TT, Kola I, Kuehn R, Lee M, Liu WQ, Motter R, Nichols NF, Power M, Robertson DW, Schenk D, Schoor M, Shopp GM, Shuck ME, Sinha S, Svensson KA, Tatsuno G, Tintrup H, Wijsman J, Wright S, McConlogue L: BACE knockout mice are healthy despite lacking the primary β-secretase activity in brain: implications for Alzheimer’s disease therapeutics. Hum Mol Genet 2001;10:1317–1324.
  63. Chang WP, Koelsch G, Wong S, Downs D, Da H, Weerasena V, Gordon B, Devasamudram T, Bilcer G, Ghosh AK, Tang J: In vivo inhibition of Aβ production by memapsin 2 (β-secretase) inhibitors. J Neurochem 2004;89:1409–1416.
  64. Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, Findlay KA, Smith TE, Murphy MP, Bulter T, Kang DE, Marquez-Sterling N, Golde TE, Koo EH: A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature 2001;414:212–216.
  65. McLaurin J, Kierstead ME, Brown ME, Hawkes CA, Lambermon MH, Phinney AL, Darabie AA, Cousins JE, French JE, Lan MF, Chen F, Wong SS, Mount HT, Fraser PE, Westaway D, George-Hyslop PS: Cyclohexanehexol inhibitors of Aβ aggregation prevent and reverse Alzheimer phenotype in a mouse model. Nat Med 2006;12:801–808.
  66. Leissring MA, Farris W, Chang AY, Walsh DM, Wu X, Sun X, Frosch MP, Selkoe DJ: Enhanced proteolysis of β-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron 2003;40:1087–1093.
  67. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P: Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999;400:173–177.
  68. Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, Chishti MA, Horne P, Heslin D, French J, Mount HT, Nixon RA, Mercken M, Bergeron C, Fraser PE, George-Hyslop P, Westaway D: A β peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature 2000;408:979–982.
  69. Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D, Connor K, Hatcher J, Hope C, Gordon M, Arendash GW: A β peptide vaccination prevents memory loss in an animal model of Alzheimer’s disease. Nature 2000;408:982–985.
  70. Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang JP, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D, Yednock T: Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 2000;6:916–919.
  71. Lau LF, Schachter JB, Seymour PA, Sanner MA: Tau protein phosphorylation as a therapeutic target in Alzheimer’s disease. Curr Top Med Chem 2002;2:395–415.
  72. Hernandez F, Lim F, Lucas JJ, Perez-Martin C, Moreno F, Avila J: Transgenic mouse models with tau pathology to test therapeutic agents for Alzheimer’s disease. Mini Rev Med Chem 2002;2:51–58.
  73. Carmeliet P: Angiogenesis in life, disease and medicine. Nature 2005;438:932–936.
  74. Sun FY, Guo X: Molecular and cellular mechanisms of neuroprotection by vascular endothelial growth factor. J Neurosci Res 2005;79:180–184.
  75. Storkebaum E, Lambrechts D, Dewerchin M, Moreno-Murciano MP, Appelmans S, Oh H, Van Damme P, Rutten B, Man WY, De Mol M, Wyns S, Manka D, Vermeulen K, Van Den Bosch L, Mertens N, Schmitz C, Robberecht W, Conway EM, Collen D, Moons L, Carmeliet P: Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS. Nat Neurosci 2005;8:85–92.
  76. Tarkowski E, Issa R, Sjogren M, Wallin A, Blennow K, Tarkowski A, Kumar P: Increased intrathecal levels of the angiogenic factors VEGF and TGF-β in Alzheimer’s disease and vascular dementia. Neurobiol Aging 2002;23:237–243.
  77. Kalaria RN, Cohen DL, Premkumar DR, Nag S, LaManna JC, Lust WD: Vascular endothelial growth factor in Alzheimer’s disease and experimental cerebral ischemia. Brain Res Mol Brain Res 1998;62:101–105.
  78. Yang SP, Bae DG, Kang HJ, Gwag BJ, Gho YS, Chae CB: Co-accumulation of vascular endothelial growth factor with β-amyloid in the brain of patients with Alzheimer’s disease. Neurobiol Aging 2004;25:283–290.
  79. Luttun A, Tjwa M, Moons L, Wu Y, Angelillo-Scherrer A, Liao F, Nagy JA, Hooper A, Priller J, De Klerck B, Compernolle V, Daci E, Bohlen P, Dewerchin M, Herbert JM, Fava R, Matthys P, Carmeliet G, Collen D, Dvorak HF, Hicklin DJ, Carmeliet P: Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med 2002;8:831–840.
  80. Autiero M, Waltenberger J, Communi D, Kranz A, Moons L, Lambrechts D, Kroll J, Plaisance S, De Mol M, Bono F, Kliche S, Fellbrich G, Ballmer-Hofer K, Maglione D, Mayr-Beyrle U, Dewerchin M, Dombrowski S, Stanimirovic D, Van Hummelen P, Dehio C, Hicklin DJ, Persico G, Herbert JM, Communi D, Shibuya M, Collen D, Conway EM, Carmeliet P: Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med 2003;9:936–943.
  81. Li X, Tjwa M, Moons L, Fons P, Noel A, Ny A, Zhou JM, Lennartsson J, Li H, Luttun A, Ponten A, Devy L, Bouche A, Oh H, Manderveld A, Blacher S, Communi D, Savi P, Bono F, Dewerchin M, Foidart JM, Autiero M, Herbert JM, Collen D, Heldin CH, Eriksson U, Carmeliet P: Revascularization of ischemic tissues by PDGF-CC via effects on endothelial cells and their progenitors. J Clin Invest 2005;115:118–127.
  82. Ponten A, Li X, Thoren P, Aase K, Sjoblom T, Ostman A, Eriksson U: Transgenic overexpression of platelet-derived growth factor-C in the mouse heart induces cardiac fibrosis, hypertrophy, and dilated cardiomyopathy. Am J Pathol 2003;163:673–682.
  83. Presta M, Dell’Era P, Mitola S, Moroni E, Ronca R, Rusnati M: Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev 2005;16:159–178.
  84. Yoshimura S, Teramoto T, Whalen MJ, Irizarry MC, Takagi Y, Qiu J, Harada J, Waeber C, Breakefield XO, Moskowitz MA: FGF-2 regulates neurogenesis and degeneration in the dentate gyrus after traumatic brain injury in mice. J Clin Invest 2003;112:1202–1210.
  85. Carlson GA, Borchelt DR, Dake A, Turner S, Danielson V, Coffin JD, Eckman C, Meiners J, Nilsen SP, Younkin SG, Hsiao KK: Genetic modification of the phenotypes produced by amyloid precursor protein overexpression in transgenic mice. Hum Mol Genet 1997;6:1951–1959.
  86. Coffin JD, Florkiewicz RZ, Neumann J, Mort-Hopkins T, Dorn GW, Lightfoot P, German R, Howles PN, Kier A, O’Toole BA: Abnormal bone growth and selective translational regulation in basic fibroblast growth factor (FGF-2) transgenic mice. Mol Biol Cell 1995;6:1861–1873.
  87. Chen H, Tung YC, Li B, Iqbal K, Grundke-Iqbal I: Trophic factors counteract elevated FGF-2-induced inhibition of adult neurogenesis. Neurobiol Aging 2006, E-pub ahead of print.
  88. Cummings BJ, Su JH, Cotman CW: Neuritic involvement within bFGF immunopositive plaques of Alzheimer’s disease. Exp Neurol 1993;124:315–325.
  89. Tatebayashi Y, Iqbal K, Grundke-Iqbal I: Dynamic regulation of expression and phosphorylation of tau by fibroblast growth factor-2 in neural progenitor cells from adult rat hippocampus. J Neurosci 1999;19:5245–5254.
  90. Lambrechts D, Storkebaum E, Morimoto M, Del Favero J, Desmet F, Marklund SL, Wyns S, Thijs V, Andersson J, van Marion I, Al Chalabi A, Bornes S, Musson R, Hansen V, Beckman L, Adolfsson R, Pall HS, Prats H, Vermeire S, Rutgeerts P, Katayama S, Awata T, Leigh N, Lang-Lazdunski L, Dewerchin M, Shaw C, Moons L, Vlietinck R, Morrison KE, Robberecht W, Van Broeckhoven C, Collen D, Andersen PM, Carmeliet P: VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nat Genet 2003;34:383–394.
  91. Pajusola K, Kunnapuu J, Vuorikoski S, Soronen J, Andre H, Pereira T, Korpisalo P, Yla-Herttuala S, Poellinger L, Alitalo K: Stabilized HIF-1α is superior to VEGF for angiogenesis in skeletal muscle via adeno-associated virus gene transfer. FASEB J 2005;19:1365–1367.
  92. Shi Y, Reitmaier B, Regenbogen J, Slowey RM, Opalenik SR, Wolf E, Goppelt A, Davidson JM: CARP, a cardiac ankyrin repeat protein, is up-regulated during wound healing and induces angiogenesis in experimental granulation tissue. Am J Pathol 2005;166:303–312.
  93. Zhong J, Eliceiri B, Stupack D, Penta K, Sakamoto G, Quertermous T, Coleman M, Boudreau N, Varner JA: Neovascularization of ischemic tissues by gene delivery of the extracellular matrix protein Del-1. J Clin Invest 2003;112:30–41.
  94. Asai J, Takenaka H, Kusano KF, Ii M, Luedemann C, Curry C, Eaton E, Iwakura A, Tsutsumi Y, Hamada H, Kishimoto S, Thorne T, Kishore R, Losordo DW: Topical sonic hedgehog gene therapy accelerates wound healing in diabetes by enhancing endothelial progenitor cell-mediated microvascular remodeling. Circulation 2006;113:2413–2424.
  95. Wang CH, Ciliberti N, Li SH, Szmitko PE, Weisel RD, Fedak PW, Al Omran M, Cherng WJ, Li RK, Stanford WL, Verma S: Rosiglitazone facilitates angiogenic progenitor cell differentiation toward endothelial lineage: a new paradigm in glitazone pleiotropy. Circulation 2004;109:1392–1400.
  96. Takeda N, Maemura K, Imai Y, Harada T, Kawanami D, Nojiri T, Manabe I, Nagai R: Endothelial PAS domain protein 1 gene promotes angiogenesis through the transactivation of both vascular endothelial growth factor and its receptor, Flt-1. Circ Res 2004;95:146–153.
  97. Ozawa K, Kondo T, Hori O, Kitao Y, Stern DM, Eisenmenger W, Ogawa S, Ohshima T: Expression of the oxygen-regulated protein ORP150 accelerates wound healing by modulating intracellular VEGF transport. J Clin Invest 2001;108:41–50.
  98. Tangkeangsirisin W, Serrero G: PC cell-derived growth factor (PCDGF/GP88, progranulin) stimulates migration, invasiveness and VEGF expression in breast cancer cells. Carcinogenesis 2004;25:1587–1592.


Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50