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Amino- and carboxyl-terminal heterogeneity of β-amyloid peptides deposited in human brain

Saido, Takaomi C., Yamao-Harigaya, Wakako, Iwatsubo, Takeshi, Kawashima, Seiichi·1996·Neuroscience Letters

DOI 10.1016/0304-3940(96)12970-0

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Abstract

We aimed to determine quantitatively the fine amino- and carboxyl-terminal structure of A beta peptides deposited in human brain using a set of 12 anti-A beta antibodies that distinguish between terminal modifications including isomerization, stereoisomerization, limited proteolysis, and cyclization. Immunochemical examination of cortical blocks from aged subjects distinguished by their total plaque load and from a young Down's syndrome patient identified the major invariantly deposited species as A beta x-42 (X = 1(D-aspartate) and 3(pyroglutamate) and/or 11(pyroglutamate)). These molecular forms, presumably representing by-products of metabolic intermediates toward degradation, are similar in being resistant to major aminopeptidases. A beta 17-42 ("p3' fragment), a major secreted form of truncated A beta with high insolubility, was found to be a minor one. A possible interpretation for these observations would be that proteolysis of A beta from its amino terminus may limit the rate of A beta catabolism.

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Cathepsin B Gene Knockout Improves Behavioral Deficits and Reduces Pathology in Models of Neurologic Disorders
Hook, G., Reinheckel, T., Ni, J., Wu, Z., Kindy, M. S., Peters, C., & HOOK, V. Y. H. (2022) · Pharmacological Reviews · doi:10.1124/pharmrev.121.000527 · Cited by 98
“The pGlu-A b (3–40/42) peptides enhance aggregation of A b peptides to result in greater neurotoxicity (Saido et al., 1996; Russo et al., 2002; Schilling et al., 2006; Nuss-baum et al., 2012).”
Background
Preferential deposition of amyloid β protein (Aβ) in the form Aβ40 in Alzheimer's disease is associated with a gene dosage effect of the apolipoprotein E E4 allele
Mann, D. M. A., Iwatsubo, T., Pickering-Brown, S. M., Owen, F., Saido, T. C., & Perry, R. H. (1997) · Neuroscience Letters · doi:10.1016/s0304-3940(96)13294-8 · Cited by 91
Self-citation
N-truncated amyloid-β oligomers induce learning impairment and neuronal apoptosis
Youssef, I., Florent‐Béchard, S., Malaplate, C., Koziel, V., Bihain, B. E., Olivier, J. L., Leininger‐Muller, B., Kriem, B., Oster, T., & Pillot, T. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.03.005 · Cited by 97
Non-canonical soluble amyloid-beta aggregates and plaque buffering: controversies and future directions for target discovery in Alzheimer’s disease
Brody, D. L., Jiang, H., Wildburger, N. C., & Esparza, T. J. (2017) · Alzheimer s Research & Therapy · doi:10.1186/s13195-017-0293-3 · Cited by 86
Oligomerization and fibril assembly of the amyloid-β protein
Roher, A. E., Baudry, J. Y., Chaney, M. O., Kuo, Y., Stine, W. B., & Emmerling, M. R. (2000) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/s0925-4439(00)00030-2 · Cited by 89
Aβ plaques
Walker, L. C. (2020) · Free Neuropathology · doi:10.17879/freeneuropathology-2020-3025 · Cited by 113
Passive Immunization against Pyroglutamate-3 Amyloid-β Reduces Plaque Burden in Alzheimer-Like Transgenic Mice: A Pilot Study
Frost, J. L., Liu, B., Kleinschmidt, M., Schilling, S., Demuth, H., & Lemere, C. A. (2012) · Neurodegenerative Diseases · doi:10.1159/000335913 · Cited by 82
Brain Pyroglutamate Amyloid-β is Produced by Cathepsin B and is Reduced by the Cysteine Protease Inhibitor E64d, Representing a Potential Alzheimer's Disease Therapeutic
Hook, G., Yu, J., Toneff, T., Kindy, M. S., & HOOK, V. Y. H. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-131370 · Cited by 87
The increased activity of BACE1 correlates with oxidative stress in Alzheimer's disease
Borghi, R., Patriarca, S., Traverso, N., Piccini, A., Storace, D., Garuti, A., Cirmena, G., Odetti, P. R., & Tabaton, M. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.05.004 · Cited by 82
Alternative pathways for production of β-amyloid peptides of Alzheimer's disease
HOOK, V. Y. H., Schechter, I., Demuth, H., & Hook, G. (2008) · Biological Chemistry · doi:10.1515/bc.2008.124 · Cited by 86
“Truncated pyroGluAb(3–40/42) peptide forms in senile plaques of AD brains Initial studies of Ab peptide forms in AD brains identified Ab(1–40) and the C-terminally extended Ab(1–42) peptide forms of Ab in amyloid plaques (Saido et al., 1995, 1996).”
Background
Amyloid-β dimers in the absence of plaque pathology impair learning and synaptic plasticity
Müller‐Schiffmann, A., Herring, A., Abdel‐Hafiz, L., Chepkova, A. N., Schäble, S., Wedel, D., Horn, A. H. C., Sticht, H., Silva, M. A. D. S., Gottmann, K., et al. (2015) · Brain · doi:10.1093/brain/awv355 · Cited by 86
Systemic Amyloid Deposits in Familial British Dementia
Ghiso, J. A., Holton, J. L., Miravalle, L., Calero, M., Lashley, T., Vidal, R., Houlden, H., Wood, N. W., Neubert, T. A., Rostagno, A. A., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m105956200 · Cited by 80
Glutaminyl Cyclase Inhibitor PQ912 Improves Cognition in Mouse Models of Alzheimer’s Disease—Studies on Relation to Effective Target Occupancy
Hoffmann, T., Meyer, A., Heiser, U. F., Kurat, S., Böhme, L., Kleinschmidt, M., Bühring, K. U., Hutter‐Paier, B., Farcher, M., Demuth, H., et al. (2017) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.117.240614 · Cited by 77
“In postmortem tissue, the pE-Ab content of deposits varies between 10 and 25% or even higher, depending on the methods of Ab extraction (Näslund et al., 1994; Lemere et al., 1996; Saido et al., 1996; Kuo et al., 1997; Portelius et al., 2010;Wu et al., 2014).”
Background
Aβ truncated species: Implications for brain clearance mechanisms and amyloid plaque deposition
Cabrera, E., Mathews, P. M., Mezhericher, E., Beach, T. G., Deng, J., Neubert, T. A., Rostagno, A. A., & Ghiso, J. A. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.07.005 · Cited by 78
“The additional loss of a negative charge occurring as a result of the cyclation of glutamate increases the β-sheet content, aggregation propensity, hydrophobicity, and resistance to enzymatic degradation of the Aβ fragments [14, 15] suggesting a contribution of these species to the disease process.”
Background
Recent advances in mass spectrometric analysis of protein deamidation
Hao, P., Adav, S. S., Gallart‐Palau, X., & Sze, S. K. (2016) · Mass Spectrometry Reviews · doi:10.1002/mas.21491 · Cited by 77
“The complete characterization of Ab-peptides and neurofibrillary tangles deposited in AD brain tissues revealed substantial quantities of deamidation (Saido et al., 1996; Shimizu et al., 2000).”
Background
Do anti-amyloid beta protein antibody cross reactivities confound Alzheimer disease research?
Hunter, S., & Brayne, C. (2017) · Journal of Negative Results in BioMedicine · doi:10.1186/s12952-017-0066-3 · Cited by 80
“AβN17 (Leu) Raised against P3 (40); recognises P3 (40) and synthetic P3 (42) peptide; epitope not well described Reactivity with insoluble, aggregated P3 (42) not confirmed [28, 42, 57]”
Background
Pyroglutamate Amyloid β (Aβ) Aggravates Behavioral Deficits in Transgenic Amyloid Mouse Model for Alzheimer Disease
Wittnam, J. L., Portelius, E., Zetterberg, H., Gustavsson, M. K., Schilling, S., Koch, B. C. P., Demuth, H., Blennow, K., Wirths, O., & Bayer, T. A. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.308601 · Cited by 77
Oxidation of Aβ and Plaque Biogenesis in Alzheimer's Disease and Down Syndrome
Head, E., Garzon-Rodriguez, W., Johnson, J. K., Lott, I. T., Cotman, C. W., & Glabe, C. (2001) · Neurobiology of Disease · doi:10.1006/nbdi.2001.0431 · Cited by 75
Inhibition of glutaminyl cyclase prevents pGlu‐Aβ formation after intracortical/hippocampal microinjection in vivo/in situ
Schilling, S., Appl, T., Hoffmann, T., Cynis, H., Schulz, K., Jagla, W., Friedrich, D., Wermann, M., Buchholz, M., Heiser, U. F., et al. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05471.x · Cited by 77
Modulation of γ-secretase by EVP-0015962 reduces amyloid deposition and behavioral deficits in Tg2576 mice
Rogers, K., Felsenstein, K. M., Hrdlicka, L., Tu, Z., Albayya, F., Lee, W., Hopp, S., Miller, M.-J., Spaulding, D., Yang, Z., et al. (2012) · Molecular Neurodegeneration · doi:10.1186/1750-1326-7-61 · Cited by 75
“Since Aβ deposits contain all lengths of Aβ peptides but are primarily composed of Aβ42 and Aβ40 [4-7], this finding is consistent with a reduction in Aβ deposition and is supportive of a potential disease”
BackgroundResultInfluential
Brain Trauma in Aged Transgenic Mice Induces Regression of Established Aβ Deposits
Nakagawa, Y., Reed, L., Nakamura, M., McIntosh, T. K., Smith, D. H., Saatman, K. E., Raghupathi, R., Clemens, J., Saido, T. C., Lee, V. M.-Y., et al. (2000) · Experimental Neurology · doi:10.1006/exnr.2000.7375 · Cited by 91
Self-citation
Posttranslational modification impact on the mechanism by which amyloid‐β induces synaptic dysfunction
Grochowska, K. M., Yuanxiang, P., Bär, J., Raman, R., Brugal, G. N., Sahu, G., Schweizer, M., Bikbaev, A. F., Schilling, S., Demuth, H., et al. (2017) · EMBO Reports · doi:10.15252/embr.201643519 · Cited by 75
Site-Specific Identification of Non-β-Strand Conformations in Alzheimer's β-Amyloid Fibrils by Solid-State NMR
Antzutkin, O. N., Balbach, J. J., & Tycko, R. (2003) · Biophysical Journal · doi:10.1016/s0006-3495(03)70057-5 · Cited by 72
Soluble amyloid beta-containing aggregates are present throughout the brain at early stages of Alzheimer’s disease
Sideris, D. I., Danial, J. S. H., Emin, D., Ruggeri, F. S., Xia, Z., Zhang, Y. P., Lobanova, E., Dakin, H., De, S., Miller, A., et al. (2021) · Brain Communications · doi:10.1093/braincomms/fcab147 · Cited by 71
“It is still unclear how comparable endogenous aggregates from Alzheimer’s disease patients are to synthetic aggregates or to those from animal models.(37,38) Far less research has been done on the aggregates in human CSF or extracted from post-mortem brain.”
Background
Acetaminophen protects hippocampal neurons and PC12 cultures from amyloid β-peptides induced oxidative stress and reduces NF-κB activation
Bisaglia, M., Venezia, V., Piccioli, P., Stanzione, S., Porcile, C., Russo, C., Mancini, F. R., Milanese, C., & Schettini, G. (2002) · Neurochemistry International · doi:10.1016/s0197-0186(01)00136-x · Cited by 71
Alzheimer’s amyloid β heterogeneous species differentially affect brain endothelial cell viability, blood‐brain barrier integrity, and angiogenesis
Parodi‐Rullán, R. M., Ghiso, J. A., Cabrera, E., Rostagno, A. A., & Fossati, S. (2020) · Aging Cell · doi:10.1111/acel.13258 · Cited by 71
“During the past decades, the presence of 40 and 42 amino acidlong Aβ peptides, their catabolic fragments, and mutated forms of the peptides, has been extensively recognized in AD and CAA brains (Cabrera et al., 2018; Masters et al., 1985; Saido et al., 1996).”
Background
Familial Danish Dementia
Tomidokoro, Y., Lashley, T., Rostagno, A., Neubert, T. A., Bojsen-Møller, M., Braendgaard, H., Plant, G., Holton, J., Frangione, B., Révész, T., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m504038200 · Cited by 68
Glutaminyl cyclase contributes to the formation of focal and diffuse pyroglutamate (pGlu)-Aβ deposits in hippocampus via distinct cellular mechanisms
Hartlage‐Rübsamen, M., Morawski, M., Waniek, A., Jäger, C., Zeitschel, U., Koch, B. C. P., Cynis, H., Schilling, S., Schliebs, R., Demuth, H., et al. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0806-2 · Cited by 66
Pyroglutamate-Modified Amyloid Beta Peptides: Emerging Targets for Alzheimer´s Disease Immunotherapy
Pérez-Garmendia, R., & Gevorkian, G. (2013) · Current Neuropharmacology · doi:10.2174/1570159x11311050004 · Cited by 65
“A N3(pE), A peptide bearing amino-terminal pyroglutamate at position 3, has been shown to be a major N-truncated/ modified constituent of intracellular, extracellular and vascular A deposits in AD brain tissue [14,15,17,28,32-35].”
BackgroundInfluential
Complement Activation in Chromosome 13 Dementias
Rostagno, A. A., Révész, T., Lashley, T., Tomidokoro, Y., Magnotti, L., Brændgaard, H., Plant, G. T., Bojsen‐Møller, M., Holton, J. L., Frangione, B., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m206448200 · Cited by 64
N‐terminal truncated pyroglutamyl β amyloid peptide Aβpy3‐42 shows a faster aggregation kinetics than the full‐length Aβ1‐42
D’Arrigo, C., Tabaton, M., & Perico, A. (2009) · Biopolymers · doi:10.1002/bip.21271 · Cited by 63
Isoglutaminyl cyclase contributes to CCL2-driven neuroinflammation in Alzheimer’s disease
Hartlage‐Rübsamen, M., Waniek, A., Meißner, J., Morawski, M., Schilling, S., Jäger, C., Kleinschmidt, M., Cynis, H., Kehlen, A., Arendt, T., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1395-2 · Cited by 62
“1 3 as N-terminal truncation and subsequent cyclization of N-terminal glutamate (Glu) into pyroglutamate (pGlu) [43, 46, 47, 56].”
Background
Intracellular accumulation of aggregated pyroglutamate amyloid beta: convergence of aging and Aβ pathology at the lysosome
Kimpe, L. D., van Haastert, E. S., Kaminari, A., Zwart, R., Rutjes, H., Hoozemans, J. J. M., & Scheper, W. (2012) · AGE · doi:10.1007/s11357-012-9403-0 · Cited by 61
“In addition to the full-length Aβ1-x peptides, various modified Aβ variants can be detected in the human brain (Saido et al. 1996).”
Background
Role of water‐soluble amyloid‐β in the pathogenesis of Alzheimer's disease
Tabaton, M., & Piccini, A. (2005) · International Journal of Experimental Pathology · doi:10.1111/j.0959-9673.2005.00428.x · Cited by 65
“Water-soluble Ab was further analysed with antibodies specific for the N-termini: B1, B2 and B3 correspond to three major species Ab 1–42, Ab py3–42, Ab py11–42, the last two forms starting with pyroglutamate in place of glutamate (Figure 1c) (Saido et al. 1996).”
Background
Urea‐based two‐dimensional electrophoresis of beta‐amyloid peptides in human plasma: Evidence for novel Aβ species
Maler, J. M., Klafki, H., Paul, S., Spitzer, P., Groemer, T. W., Henkel, A. W., Esselmann, H., Lewczuk, P., Kornhuber, J., & Wiltfang, J. (2007) · PROTEOMICS · doi:10.1002/pmic.200700311 · Cited by 61
Astrocytes and microglia but not neurons preferentially generate N-terminally truncated Aβ peptides
Oberstein, T. J., Spitzer, P., Klafki, H., Linning, P., Neff, F., Knölker, H., Lewczuk, P., Wiltfang, J., Kornhuber, J., & Maler, J. M. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.08.031 · Cited by 64
Molecular Dating of Senile Plaques in the Brains of Individuals with Down Syndrome and in Aged Dogs
Azizeh, B. Y., Head, E., Ibrahim, M. A., Torp, R., Tenner, A. J., Kim, R. C., Lott, I. T., & Cotman, C. W. (2000) · Experimental Neurology · doi:10.1006/exnr.2000.7359 · Cited by 58
Cerebral amyloidosis, amyloid angiopathy, and their relationship to stroke and dementia
Ghiso, J. A., & Frangione, B. (2001) · Journal of Alzheimer s Disease · doi:10.3233/jad-2001-3110 · Cited by 58
“peptides derived from Alzheimer Aβ [35,43,52].”

Authors: Saido, T. C., Yamao-Harigaya, W., Iwatsubo, T., & Kawashima, S.
Affiliations: Tokyo Metropolitan Institute of Medical Science (JP)
The University of Tokyo (JP)
Corresponding author: Saido, Takaomi C.
ORCID: Saido, Takaomi C.
Iwatsubo, Takeshi
Venue: Neuroscience Letters
Publisher: Elsevier BV
Published: 1996-09
Volume: 215
Issue: 3
Pages: 173-176
ISSN: 0304-3940 (ISSN-L)
DOI: 10.1016/0304-3940(96)12970-0
OpenAlex: W2012288880
Cited by: 270
References: 11
Citations by year: 2026: 3 · 2025: 3 · 2024: 11 · 2023: 11 · 2022: 4 · 2021: 7 · 2020: 14 · 2019: 6 · 2018: 6 · 2017: 14 · 2016: 4 · 2015: 9 · 2014: 14 · 2013: 15 · 2012: 8
FWCI: 5.63
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Neuroscience Letters (publishedVersion)
PubMed (publishedVersion)
Funders: Uehara Memorial Foundation
Ministry of Education, Culture, Sports, Science and Technology
Naito Foundation
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: amyloid-beta, amyloid plaques, terminal modification, pyroglutamic acid, D-aspartate, anti-amyloid antibodies, Down syndrome, proteolysis, human brain
MeSH terms: Adult, Alzheimer Disease, Brain, Humans, Blotting, Western, Amyloid beta-Protein Precursor

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Amino- and carboxyl-terminal heterogeneity of β-amyloid peptides deposited in human brain

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