Background: N-terminally truncated and modified pyroglutamate-3 amyloid-β protein (pE3-Aβ) is present in most, if not all, cerebral plaque and vascular amyloid deposits in human Alzheimer’s disease (AD). pE3-Aβ deposition is also found in AD-like transgenic (tg) mouse brain, albeit in lesser quantities than general Aβ. pE3-Aβ resists degradation, is neurotoxic, and may act as a seed for Aβ aggregation. Objective: We sought to determine if pE3-Aβ removal by passive immunization with a highly specific monoclonal antibody (mAb) impacts pathogenesis in a mouse model of Alzheimer’s amyloidosis. Methods: APPswe/PS1ΔE9 tg mice were given weekly intraperitoneal injections of a new anti-pE3-Aβ mAb (mAb07/1) or PBS from 5.8 to 13.8 months of age (prevention) or from 23 to 24.7 months of age (therapeutic). Multiple forms of cerebral Aβ were quantified pathologically and biochemically. Gliosis and microhemorrhage were examined. Results: Chronic passive immunization with an anti-pE3-Aβ mAb significantly reduced total plaque deposition and appeared to lower gliosis in the hippocampus and cerebellum in both the prevention and therapeutic studies. Insoluble Aβ levels in hemibrain homogenates were not significantly different between immunized and control mice. Microhemorrhage was not observed with anti-pE3-Aβ immunotherapy. Conclusions: Selective removal of pE3-Aβ lowered general Aβ plaque deposition suggesting a pro-aggregation or seeding role for pE3-Aβ.
© 2012 S. Karger AG, Basel
- Alzheimer’s disease
- Pyroglutamate-3 amyloid-β
- Monoclonal antibody
- Transgenic mice
- Selkoe DJ: Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 2001;81:741–766.
- Saido TC, Iwatsubo T, Mann DMA, Shimada H, Ihara Y, Kawashima S: Dominant and differential deposition of distinct β-amyloid peptide species, AβN3(p3), in senile plaques. Neuron 1995;14:457–466.
- Lemere CA, Blusztajn JK, Yamaguchi H, Wisniewski T, Saido TC, Selkoe DJ: Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol Dis 1996;3:16–32.
- Lemere CA, Lopera F, Kosik KS, Lendon CL, Ossa J, Saido TC, Yamaguchi H, Ruiz A, Martinez A, Madrigal L, Hincapie L, Arango-L JC, Anthony DC, Koo E, Goate A, Selkoe DJ, Arango-V JC: The E280A presenilin 1 Alzheimer mutation produces increased Aβ42 deposition and severe cerebellar pathology. Nat Med 1996;2:1146–1150.
- Miravalle L, Calero M, Takao M, Roher A, Ghetti B, Vidal R: Amino-terminally truncated Aβ peptide species are the main component of cotton wool plaques. Biochemistry 2005;44:10810–10821.
- Wirths O, Bethge T, Marcello A, Harmeier A, Jawhar S, Lucassen P, Malthaup G, Brody DL, Esparza T, Ingelsson M, Kalimo H, Lannsfelt L, Bayer TA: Pyroglutamate Abeta pathology in APP/PS1KO mice, sporadic and familial Alzheimer’s disease cases. J Neural Transm 2010;117:85–96.
- Schilling S, Hoffmann T, Manhart S, Hoffmann M, Demuth H: Glutaminyl cyclases unfold glutamyl cyclase activity under mild acid conditions. FEBS Lett 2004;563:191–196.
- Saido TC, Yamao-Harigaya W, Iwatsubo T, Kawashima S: Amino- and carboxyl-terminal heterogeneity of beta-amyloid peptides deposited in human brain. Neurosci Lett 1996;215:173–176.
- Schilling S, Lauber T, Schaupp M, Manhart S, Scheel E, Bohm G, Demuth H-U: On the seeding and oligomerization of the pGlu-amyloid peptides (in vitro). Biochemistry 2006;45:12393–12399.
- He W, Barrow C: The Aβ 3-pyroglutamyl and 11-pyroglutamyl peptides found in senile plaques have greater β-sheet forming and aggregation propensities in vitro than full length Aβ. Biochemistry 1999;38:10871–10877.
- Wirths O, Breyhan H, Cynis H, Schilling S, Demuth H-U, Bayer T: Intraneuronal pyroglutamate-Abeta 3–42 triggers neurodegeneration and lethal neurological deficits in a transgenic mouse model. Acta Neuropathol 2009;118:487–496.
- Guntert A, Dobeli H, Bohrmann B: High sensitivity analysis of amyloid-beta peptide composition in amyloid deposits from human and PS2APP mouse brain. Neuroscience 2006;143:461–475.
- Piccini A, Zanusso G, Borghi R, Noviello C, Monaco S, Russo R, Damonte G, Armirotti A, Gelati M, Giordano R, Zambenedetti P, Russo C, Ghetti B, Tabaton M: Association of a presenilin 1 S170F mutation with a novel Alzheimer disease molecular phenotype. Arch Neurol 2007;64:738–745.
- Piccini A, Russo C, Gliozzi A, Relini A, Vitali A, Borghi R, Giliberto L, Armirotti A, D’Arrigo C, Bachi A, Cattaneo A, Canale C, Torrassa S, Saido T, Markesbery W, Gambetti P, Tabaton M: β-Amyloid is different in normal aging and in Alzheimer’s disease. J Biol Chem 2005;280:34186–34192.
- Cynis J, Scheel E, Saido TC, Schilling S, Demuth HU: Amyloidogenic processing of the amyloid precursor protein: evidence of a pivotal role of glutaminyl cyclase in generation of pyroglutamate-modified amyloid-beta. Biochemistry 2008;47:7405–7413.
- Jankowsky J, Fadale D, Anderson J, Xu G, Gonzales V, Jenkins N, Copeland N, Lee M, Younkin L, Wagner S, Younkin S, Borchelt D: Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet 2004;13:159–170.
- Garcia-Alloza M, Robbins E, Zhang-Nunes S, Purcell S, Betensky R, Raju S, Prada C, Greenberg S, Bacskai B, Frosch M: Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer’s disease. Neurobiol Dis 2006;24:516–524.
- Lemere CA, Spooner ET, Leverone JF, Mori C, Clements JD: Intranasal immunotherapy for the treatment of Alzheimer’s disease: Escherichia coli LT and LT(R192G) as mucosal adjuvants. Neurobiol Aging 2002;23:991–1000.
- Schilling S, Zeitschel U, Hoffmann T, Heiser U, Franke M, Kehlen A, Holzer M, Hutter-Paier B, Prokesch M, Windisch M, Jagla W, Schlenzig D, Lindner C, Rudolph T, Reuter G, Cynis H, Montage D, Demuth H-U, Rossner S: Glutaminyl cyclase inhibition attenuates pyroglutamate Aβ and Alzheimer’s disease-like pathology. Nat Med 2008;14:1106–1111.
- Wirths O, Erck C, Martens H, Harmeier A, Geumann C, Jawhar S, Kumar S, Multhaup G, Walter J, Ingelsson M, Degerman-Gunnarsson M, Kalimo H, Huitinga I, Lannfelt L, Bayer TA: Identification of low molecular weight pyroglutamate Aβ oligomers in Alzheimer disease. J Biol Chem 2010;285:41517–41524.
Cynthia A. Lemere, PhD
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Boston, MA 02115 (USA)
Tel. +1 617 525 5214, E-Mail email@example.com
J.L. Frost and B. Liu contributed equally to this article.
Received: September 15, 2011
Accepted after revision: December 18, 2011
Published online: February 16, 2012
Number of Print Pages : 6
Number of Figures : 3, Number of Tables : 1, Number of References : 20
Vol. 10, No. 1-4, Year 2012 (Cover Date: April 2012)
Journal Editor: Nitsch R.M. (Zürich), Hock C. (Zürich)
ISSN: 1660-2854 (Print), eISSN: 1660-2862 (Online)
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