Journal Mobile Options
Table of Contents
Vol. 4, No. 2-3, 2007
Issue release date: June 2007
Neurodegenerative Dis 2007;4:127–135

BACE1 and Mutated Presenilin-1 Differently Modulate Aβ40 and Aβ42 Levels and Cerebral Amyloidosis in APPDutch Transgenic Mice

Herzig M.C. · Paganetti P. · Staufenbiel M. · Jucker M.
aDepartment of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; bDepartment of Neuropathology, Institute of Pathology, University of Basel, and cNervous System Research, Novartis Institutes for Biomedical Research, Basel, Switzerland

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


APPDutch transgenic (tg) mice develop cerebral amyloid angiopathy (CAA) that consists mainly of AβDutch40, with virtually no parenchymal amyloid plaques. To modulate cerebral amyloidosis, we crossbred APPDutch mice with either BACE1 tg mice to increase total AβDutch, or with G384A-mutated PS1 tg mice to elevate the ratio of AβDutch42 to AβDutch40. We analyzed all mice at 22 months of age. Compared to APPDutch mice, double-tg APPDutch/BACE1 mice revealed increased CAA mainly due to extensive vascular amyloid accumulation in the thalamus. In addition, they developed parenchymal amyloid in cortex and subiculum. In contrast, APPDutch/G384A-PS1 mice showed extensive, predominantly parenchymal amyloid throughout the entire brain, interestingly, even in the thalamus. The amyloid, composed largely of AβDutch42, was different compared to that in APPDutch/BACE1 mice which was composed mainly of AβDutch40. In summary, these mouse models reveal a broad variety and region-specificity of parenchymal versus vascular cerebral amyloid. This is partially explained by the absolute amount of neuronally produced AβDutch42 and AβDutch40 and ratio between the two. We conclude that the absolute levels of Aβ in combination with the ratio of Aβ42 to Aβ40 play a key role in determining the cerebral compartment and brain region in which Aβ is deposited.

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.


  1. 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 ML, Staufenbiel M, Mathews PM, Jucker M: Aβ is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat Neurosci 2004;7:954–960.
  2. Maat-Schieman M, Roos R, van Duinen S: Hereditary cerebral hemorrhage with amyloidosis-Dutch type. Neuropathology 2005;25:288–297.
  3. Haass C: Take five–BACE and the γ-secretase quartet conduct Alzheimer’s amyloid β-peptide generation. EMBO J 2004;23:483–488.
  4. Vassar R, Citron M: Aβ-generating enzymes: recent advances in β- and γ-secretase research. Neuron 2000;27:419–422.
  5. 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.
  6. Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Seubert P, Davis A, Kholodenko D, Motter R, Sherrington R, Perry B, Yao H, Strome R, Lieberburg I, Rommens J, Kim S, Schenk D, Fraser P, St George Hyslop P, Selkoe DJ: Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice. Nat Med 1997;3:67–72.
  7. Hardy J, Selkoe DJ: The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002;297:353–356.
  8. Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, Vigo-Pelfrey C, Lieberburg I, Selkoe DJ: Mutation of the β-amyloid precursor protein in familial Alzheimer’s disease increases β-protein production. Nature 1992;360:672–674.
  9. Yang LB, Lindholm K, Yan R, Citron M, Xia W, Yang XL, Beach T, Sue L, Wong P, Price D, Li R, Shen Y: Elevated β-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat Med 2003;9:3–4.
  10. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M: β-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999;286:735–741.
  11. Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WR, Buhl AE, Carter DB, Tomasselli AG, Parodi LA, Heinrikson RL, Gurney ME: Membrane-anchored aspartyl protease with Alzheimer’s disease β-secretase activity. Nature 1999;402:533–537.
  12. Bodendorf U, Danner S, Fischer F, Stefani M, Sturchler-Pierrat C, Wiederhold KH, Staufenbiel M, Paganetti P: Expression of human β-secretase in the mouse brain increases the steady-state level of β-amyloid. J Neurochem 2002;80:799–806.
  13. Sturchler-Pierrat C, Wiederhold KH, Danner S, Mistl C, Zigerli D, Abramowski D, Staufenbiel M, Sommer B: Acceleration of AD-type pathology depends on presenilin 1 point mutation in APPxPS1 double transgenic mice. Soc Neurosci Abstr, vol 25, Program No 519.2, 1999.
  14. Lüthi A, Van der Putten H, Botteri FM, Mansuy IM, Meins M, Frey U, Sansig G, Portet C, Schmutz M, Schroder M, Nitsch C, Laurent JP, Monard D: Endogenous serine protease inhibitor modulates epileptic activity and hippocampal long-term potentiation. J Neurosci 1997;17:4688–4699.
  15. Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, Ledermann B, Burki K, Frey P, Paganetti PA, Waridel C, Calhoun ME, Jucker M, Probst A, Staufenbiel M, Sommer B: Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA 1997;94:13287–13292.
  16. Saido TC, Yokota M, Maruyama K, Yamao-Harigaya W, Tani E, Ihara Y, Kawashima S: Spatial resolution of the primary β-amyloidogenic process induced in postischemic hippocampus. J Biol Chem 1994;269:15253–15257.
  17. Klafki HW, Wiltfang J, Staufenbiel M: Electrophoretic separation of βA4 peptides (1–40) and (1–42). Anal Biochem 1996;237:24–29.
  18. Wiltfang J, Smirnov A, Schnierstein B, Kelemen G, Matthies U, Klafki HW, Staufenbiel M, Huther G, Ruther E, Kornhuber J: Improved electrophoretic separation and immunoblotting of β-amyloid (Aβ) peptides 1–40, 1–42, and 1–43. Electrophoresis 1997;18:527–532.
  19. Winkler DT, Bondolfi L, Herzig MC, Jann L, Calhoun ME, Wiederhold KH, Tolnay M, Staufenbiel M, Jucker M: Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy. J Neurosci 2001;21:1619–1627.
  20. Mohajeri MH, Saini KD, Nitsch RM: Transgenic BACE expression in mouse neurons accelerates amyloid plaque pathology. J Neural Transm 2004;111:413–425.
  21. Lee EB, Zhang B, Liu K, Greenbaum EA, Doms RW, Trojanowski JQ, Lee VM: BACE overexpression alters the subcellular processing of APP and inhibits Aβ deposition in vivo. J Cell Biol 2005;168:291–302.
  22. Willem M, Dewachter I, Smyth N, Van Dooren T, Borghgraef P, Haass C, Van Leuven F: β-site amyloid precursor protein cleaving enzyme 1 increases amyloid deposition in brain parenchyma but reduces cerebrovascular amyloid angiopathy in aging BACE × APP[V717I] double-transgenic mice. Am J Pathol 2004;165:1621–1631.
  23. Rockenstein E, Mante M, Alford M, Adame A, Crews L, Hashimoto M, Esposito L, Mucke L, Masliah E: High β-secretase activity elicits neurodegeneration in transgenic mice despite reductions in amyloid-β levels: implications for the treatment of Alzheimer disease. J Biol Chem 2005;280:32957–32967.
  24. Ozmen L, Woolley M, Albientz A, Miss MT, Nelboeck P, Malherbe P, Czech C, Grüninger-Leitch F, Brockhaus M, Ballard T, Jacobsen H: BACE/APPV717F double-transgenic mice develop cerebral amyloidosis and inflammation. Neurodegenerative Dis 2005;2:284–298.
  25. Chiocco MJ, Kulnane LS, Younkin L, Younkin S, Evin G, Lamb BT: Altered amyloid-β metabolism and deposition in genomic-based β-secretase transgenic mice. J Biol Chem 2004;279:52535–52542.
  26. Herzig MC, Van Nostrand WE, Jucker M: Mechanism of cerebral β-amyloid angiopathy: murine and cellular models. Brain Pathol 2006;16:40–54.
  27. Borchelt DR, Ratovitski T, van Lare 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.
  28. 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.
  29. 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.
  30. Radde R, Bolmont T, Kaeser SA, Coomaraswamy J, Lindau D, Stoltze L, Calhoun ME, Jaggi F, Wolburg H, Gengler S, Haass C, Ghetti B, Czech C, Holscher C, Mathews PM, Jucker M: Aβ42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep 2006.
  31. Lleo A, Berezovska O, Growdon JH, Hyman BT: Clinical, pathological, and biochemical spectrum of Alzheimer disease associated with PS-1 mutations. Am J Geriatr Psychiatry 2004;12:146–156.
  32. Cruts M, Backhovens H, Wang SY, Van Gassen G, Theuns J, De Jonghe CD, Wehnert A, De Voecht J, De Winter G, Cras P, et al.: Molecular genetic analysis of familial early-onset Alzheimer’s disease linked to chromosome 14q24.3. Hum Mol Genet 1995;4:2363–2371.
  33. Tanahashi H, Kawakatsu S, Kaneko M, Yamanaka H, Takahashi K, Tabira T: Sequence analysis of presenilin-1 gene mutation in Japanese Alzheimer’s disease patients. Neurosci Lett 1996;218:139–141.
  34. 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.
  35. De Jonghe C, Cras P, Vanderstichele H, Cruts M, Vanderhoeven I, Smouts I, Vanmechelen E, Martin JJ, Hendriks L, Van Broeckhoven C: Evidence that Aβ42 plasma levels in presenilin-1 mutation carriers do not allow for prediction of their clinical phenotype. Neurobiol Dis 1999;6:280–287.
  36. Tsubuki S, Takaki Y, Saido TC: Dutch, Flemish, Italian, and Arctic mutations of APP and resistance of Aβ to physiologically relevant proteolytic degradation. Lancet 2003;361:1957–1958.
  37. Morelli L, Llovera R, Gonzalez SA, Affranchino JL, Prelli F, Frangione B, Ghiso J, Castano EM: Differential degradation of amyloid β genetic variants associated with hereditary dementia or stroke by insulin-degrading enzyme. J Biol Chem 2003;278:23221–23226.
  38. Deane R, Wu Z, Sagare A, Davis J, Du Yan S, Hamm K, Xu F, Parisi M, LaRue B, Hu HW, Spijkers P, Guo H, Song X, Lenting PJ, Van Nostrand WE, Zlokovic BV: LRP/amyloid β-peptide interaction mediates differential brain efflux of Aβ isoforms. Neuron 2004;43:333–344.
  39. Murakami K, Irie K, Morimoto A, Ohigashi H, Shindo M, Nagao M, Shimizu T, Shirasawa T: Neurotoxicity and physicochemical properties of Aβ mutant peptides from cerebral amyloid angiopathy: implication for the pathogenesis of cerebral amyloid angiopathy and Alzheimer’s disease. J Biol Chem 2003;278:46179–46187.
  40. Weller RO, Massey A, Newman TA, Hutchings M, Kuo YM, Roher AE: Cerebral amyloid angiopathy: amyloid β accumulates in putative interstitial fluid drainage pathways in Alzheimer’s disease. Am J Pathol 1998;153:725–733.
  41. Davis J, Xu F, Deane R, Romanov G, Previti ML, Zeigler K, Zlokovic BV, Van Nostrand WE: Early-onset and robust cerebral microvascular accumulation of amyloid β-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid β-protein precursor. J Biol Chem 2004;279:20296–20306.
  42. Miao J, Xu F, Davis J, Otte-Holler I, Verbeek MM, Van Nostrand WE: Cerebral microvascular amyloid β protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid β precursor protein. Am J Pathol 2005;167:505–515.

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