Top

Published in:

01-08-2006 | Original Paper

Characterization of Aβ11-40/42 peptide deposition in Alzheimer’s disease and young Down’s syndrome brains: implication of N-terminally truncated Aβ species in the pathogenesis of Alzheimer’s disease

Authors: Kangning Liu, Ingrid Solano, David Mann, Cynthia Lemere, Marc Mercken, John Q. Trojanowski, Virginia M.-Y. Lee

Published in: Acta Neuropathologica | Issue 2/2006

Abstract

Senile plaques (SPs), one of two defining lesions of Alzheimer’s disease (AD), are composed of a mixture of full-length Aβ1-40/42, and N- or C-terminally truncated Aβ peptides, including Aβ11-40/42. Sequential proteolysis of amyloid precursor protein (APP) by β- and γ-secretases produces Aβ1-40/42, but β-site APP-cleaving enzyme 1 (BACE1), the major β-secretase, also generates Aβ11-40/42, and BACE1 overexpression in cultured cells results primarily in secretion of Aβ11-40/42. The ratio of Aβ11-40/42 to Aβ1-40/42 depends on the ratio of BACE1 to APP, and Aβ11-40/42 can be generated from both full-length APP and its carboxy-terminal fragment (C99). Here, we investigated the role of Aβ11-40/42 in the pathogenesis of AD and Down’s syndrome (DS) brains. We demonstrated significant amount of Aβ11-42 in DS brains by Western blots. While pyroAβ11-42-modified Aβ species existed predominantly in mature SP cores in AD brain sections, both unmodified free Aβ11-40 and pyro-modified Aβ11-40 are detected in vascular amyloid deposits by immunohistochemistry. Using novel ELISAs for quantifying free Aβ11-40/42 and pyroAβ11-40/42, we showed that insoluble Aβ11-42 predominated in extracts of AD and DS brains. This is the first systematic study of Aβ11-40/42 in neurodegenerative Aβ amyloidosis implicating Aβ11-40/42 in SP formation of AD and DS brains. The detection of Aβ11-42 in young DS brain suggests an early role for this N-terminally truncated Aβ peptide in the pathogenesis of SPs in AD and DS.

Acquati F, Accarino M, Nucci C, Fumagalli P, Jovine L, Ottolenghi S, Taramelli R (2000) The gene encoding DRAP (BACE2), a glycosylated transmembrane protein of the aspartic protease family, maps to the down critical region. FEBS Lett 468(1):59–64PubMedCrossRef

Barbiero L, Benussi L, Ghidoni R, Alberici A, Russo C, Schettini G, Pagano SF, Parati EA, Mazzoli F, Nicosia F, Signorini S, Feudatari E, Binetti G (2003) BACE-2 is overexpressed in Down’s syndrome. Exp Neurol 182(2):335–345PubMedCrossRef

Bennett BD, Babu-Khan S, Loeloff R, Louis JC, Curran E, Citron M, Vassar R (2000) Expression analysis of BACE2 in brain and peripheral tissues. J Biol Chem 275(27):20647–20651PubMedCrossRef

Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL, Wong PC (2001) BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat Neurosci 4(3):233–234PubMedCrossRef

Creemers JW, Ines DD, Plets E, Serneels L, Taylor NA, Multhaup G, Craessaerts K, Annaert W, De Strooper B (2001) Processing of beta-secretase by furin and other members of the proprotein convertase family. J Biol Chem 276(6):4211–4217PubMedCrossRef

DeMattos RB, O’Dell MA, Parsadanian M, Taylor JW, Harmony JA, Bales KR, Paul SM, Aronow BJ, Holtzman DM (2002) Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 99(16):10843–10848PubMedCrossRef

Dominguez D, Tournoy J, Hartmann D, Huth T, Cryns K, Deforce S, Serneels L, Camacho IE, Marjaux E, Craessaerts K, Roebroek AJ, Schwake M, D’Hooge R, Bach P, Kalinke U, Moechars D, Alzheimer C, Reiss K, Saftig P, De Strooper B (2005) Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice. J Biol Chem 280(35):30797–30806PubMedCrossRef

El Mouedden M, Vandermeeren M, Meert T, Mercken M (2005) Development of a specific ELISA for the quantitative study of amino-terminally truncated beta-amyloid peptides. J Neurosci Methods 145(1–2):97–105PubMedCrossRef

Farzan M, Schnitzler CE, Vasilieva N, Leung D, Choe H (2000) BACE2, a beta-secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein. Proc Natl Acad Sci USA 97(17):9712–9717PubMedCrossRef

10.

Fukumoto H, Cheung BS, Hyman BT, Irizarry MC (2002) Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol 59(9):1381–1389PubMedCrossRef

11.

Holsinger RM, McLean CA, Beyreuther K, Masters CL, Evin G (2002) Increased expression of the amyloid precursor beta-secretase in Alzheimer’s disease. Ann Neurol 51(6):783–786PubMedCrossRef

12.

Hosoda R, Saido TC, Otvos L Jr, Arai T, Mann DM, Lee VM, Trojanowski JQ, Iwatsubo T (1998) Quantification of modified amyloid beta peptides in Alzheimer disease and Down syndrome brains. J Neuropathol Exp Neurol 57(11):1089–1095PubMedCrossRef

13.

Huse JT, Liu K, Pijak DS, Carlin D, Lee VM, Doms RW (2002) Beta-secretase processing in the trans-Golgi network preferentially generates truncated amyloid species that accumulate in Alzheimer’s disease brain. J Biol Chem 277(18):16278–16284PubMedCrossRef

14.

Hussain I, Powell DJ, Howlett DR, Chapman GA, Gilmour L, Murdock PR, Tew DG, Meek TD, Chapman C, Schneider K, Ratcliffe SJ, Tattersall D, Testa TT, Southan C, Ryan DM, Simmons DL, Walsh FS, Dingwall C, Christie G (2000) ASP1 (BACE2) cleaves the amyloid precursor protein at the beta-secretase site. Mol Cell Neurosci 16(5):609–619PubMedCrossRef

15.

Iwatsubo T, Mann DM, Odaka A, Suzuki N, Ihara Y (1995) Amyloid beta protein (A beta) deposition: A beta 42(43) precedes A beta 40 in Down syndrome. Ann Neurol 37(3):294–299PubMedCrossRef

16.

Iwatsubo T, Saido TC, Mann DM, Lee VM, Trojanowski JQ (1996) Full-length amyloid-beta (1-42(43)) and amino-terminally modified and truncated amyloid-beta 42(43) deposit in diffuse plaques. Am J Pathol 149(6):1823–1830PubMed

17.

Jarrett JT, Berger EP, Lansbury PT Jr (1993) The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease. Biochemistry 32(18):4693–4697PubMedCrossRef

18.

Kawarabayashi T, Younkin LH, Saido TC, Shoji M, Ashe KH, Younkin SG (2001) Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer’s disease. J Neurosci 21(2):372–381PubMed

19.

Kuo YM, Emmerling MR, Woods AS, Cotter RJ, Roher AE (1997) Isolation, chemical characterization, and quantitation of A beta 3-pyroglutamyl peptide from neuritic plaques and vascular amyloid deposits. Biochem Biophys Res Commun 237(1):188–191PubMedCrossRef

20.

Lemere CA, Blusztajn JK, Yamaguchi H, Wisniewski T, Saido TC, Selkoe DJ (1996) Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol Dis 3(1):16–32PubMedCrossRef

21.

Leverenz JB, Raskind MA (1998) Early amyloid deposition in the medial temporal lobe of young Down syndrome patients: a regional quantitative analysis. Exp Neurol 150(2):296–304PubMedCrossRef

22.

Liu K, Doms RW, Lee VM (2002) Glu11 site cleavage and N-terminally truncated A beta production upon BACE overexpression. Biochemistry 41(9):3128–3136PubMedCrossRef

23.

Luo Y, Bolon B, Kahn S, Bennett BD, Babu-Khan S, Denis P, Fan W, Kha H, Zhang J, Gong Y, Martin L, Louis JC, Yan Q, Richards WG, Citron M, Vassar R (2001) Mice deficient in BACE1, the Alzheimer’s beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat Neurosci 4(3):231–232PubMedCrossRef

24.

Mori C, Spooner ET, Wisniewsk KE, Wisniewski TM, Yamaguch H, Saido TC, Tolan DR, Selkoe DJ, Lemere CA (2002) Intraneuronal Abeta42 accumulation in Down syndrome brain. Amyloid 9(2):88–102PubMed

25.

Motonaga K, Itoh M, Becker LE, Goto Y, Takashima S (2002) Elevated expression of beta-site amyloid precursor protein cleaving enzyme 2 in brains of patients with Down syndrome. Neurosci Lett 326(1):64–66PubMedCrossRef

26.

Naslund J, Schierhorn A, Hellman U, Lannfelt L, Roses AD, Tjernberg LO, Silberring J, Gandy SE, Winblad B, Greengard P (1994) Relative abundance of Alzheimer A beta amyloid peptide variants in Alzheimer disease and normal aging. Proc Natl Acad Sci USA 91(18):8378–8382PubMedCrossRef

27.

Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, Stenh C, Luthman J, Teplow DB, Younkin SG, Naslund J, Lannfelt L (2001) The ‘Arctic’ APP mutation (E693G) causes Alzheimer’s disease by enhanced Abeta protofibril formation. Nat Neurosci 4(9):887–893PubMedCrossRef

28.

Pike CJ, Overman MJ, Cotman CW (1995) Amino-terminal deletions enhance aggregation of beta-amyloid peptides in vitro. J Biol Chem 270(41):23895–23898PubMedCrossRef

29.

Russo C, Schettini G, Saido TC, Hulette C, Lippa C, Lannfelt L, Ghetti B, Gambetti P, Tabaton M, Teller JK (2000) Presenilin-1 mutations in Alzheimer’s disease. Nature 405(6786):531–532PubMedCrossRef

30.

Russo C, Salis S, Dolcini V, Venezia V, Song XH, Teller JK, Schettini G (2001) Amino-terminal modification and tyrosine phosphorylation of [corrected] carboxy-terminal fragments of the amyloid precursor protein in Alzheimer’s disease and Down’s syndrome brain. Neurobiol Dis 8(1):173–180PubMedCrossRef

31.

Saido TC, Iwatsubo T, Mann DM, Shimada H, Ihara Y, Kawashima S (1995) Dominant and differential deposition of distinct beta-amyloid peptide species, A beta N3(pE), in senile plaques. Neuron 14(2):457–466PubMedCrossRef

32.

Sudoh S, Kawamura Y, Sato S, Wang R, Saido TC, Oyama F, Sakaki Y, Komano H, Yanagisawa K (1998) Presenilin 1 mutations linked to familial Alzheimer’s disease increase the intracellular levels of amyloid beta-protein 1-42 and its N-terminally truncated variant(s) which are generated at distinct sites. J Neurochem 71(4):1535–1543PubMedCrossRef

33.

Tekirian TL (2001) Commentary: Abeta N-terminal isoforms: critical contributors in the course of AD pathophysiology. J Alzheimers Dis 3(2):241–248PubMed

34.

Teller JK, Russo C, DeBusk LM, Angelini G, Zaccheo D, Dagna-Bricarelli F, Scartezzini P, Bertolini S, Mann DM, Tabaton M, Gambetti P (1996) Presence of soluble amyloid beta-peptide precedes amyloid plaque formation in Down’s syndrome. Nat Med 2(1):93–95PubMedCrossRef

35.

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 (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286(5440):735–741PubMedCrossRef

36.

Wiltfang J, Esselmann H, Cupers P, Neumann M, Kretzschmar H, Beyermann M, Schleuder D, Jahn H, Ruther E, Kornhuber J, Annaert W, De Strooper B, Saftig P (2001) Elevation of beta-amyloid peptide 2-42 in sporadic and familial Alzheimer’s disease and its generation in PS1 knockout cells. J Biol Chem 276(46):42645–42657PubMedCrossRef

37.

Wiltfang J, Esselmann H, Bibl M, Smirnov A, Otto M, Paul S, Schmidt B, Klafki HW, Maler M, Dyrks T, Bienert M, Beyermann M, Ruther E, Kornhuber J (2002) Highly conserved and disease-specific patterns of carboxyterminally truncated Abeta peptides 1-37/38/39 in addition to 1-40/42 in Alzheimer’s disease and in patients with chronic neuroinflammation. J Neurochem 81(3):481–496PubMedCrossRef

38.

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 (1999) Membrane-anchored aspartyl protease with Alzheimer’s disease beta-secretase activity. Nature 402(6761):533–537PubMedCrossRef

39.

Yan R, Munzner JB, Shuck ME, Bienkowski MJ (2001) BACE2 functions as an alternative alpha-secretase in cells. J Biol Chem 276(36):34019–34027PubMedCrossRef

Title: Characterization of Aβ11-40/42 peptide deposition in Alzheimer’s disease and young Down’s syndrome brains: implication of N-terminally truncated Aβ species in the pathogenesis of Alzheimer’s disease
Authors: Kangning Liu
Ingrid Solano
David Mann
Cynthia Lemere
Marc Mercken
John Q. Trojanowski
Virginia M.-Y. Lee
Publication date: 01-08-2006
Publisher: Springer-Verlag
Published in: Acta Neuropathologica / Issue 2/2006
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-006-0077-5

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Characterization of Aβ11-40/42 peptide deposition in Alzheimer’s disease and young Down’s syndrome brains: implication of N-terminally truncated Aβ species in the pathogenesis of Alzheimer’s disease

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2006

Early involvement of small inhibitory cortical interneurons in Alzheimer’s disease

Diffuse beta-amyloid plaques and hyperphosphorylated tau are unrelated processes in aged dogs with behavioral deficits

Chemokine expression by astrocytes plays a role in microglia/macrophage activation and subsequent neurodegeneration in secondary progressive multiple sclerosis

Rimmed vacuoles with beta-amyloid and tau protein deposits in the muscle of children with hereditary myopathy

Relapsing polychondritis with features of dementia with Lewy bodies

Ex vivo therapy of malignant melanomas transplanted into organotypic brain slice cultures using inhibitors of histone deacetylases