Amyloid β Protein Starting Pyroglutamate at Position 3 Is a Major Component of the Amyloid Deposits in the Alzheimer's Disease Brain
Abstract
The amyloid beta protein (Abeta) deposited in the Alzheimer's disease (AD) brain is heterogeneous at both its amino and carboxyl termini. Recent studies of the genetic forms of AD indicate that the aggregation and deposition of Abeta42 may be a common initiating event in all forms of AD. Here, we analyzed the amino termini of the Abeta species deposited in the AD brain, focusing specifically on species with amino-terminal pyroglutamate at position 3 (Abeta3(pE)). Immunocytochemical analysis of AD brains with an antibody specific for Abeta3(pE) confirmed that these species deposit in blood vessels and senile plaques. Using specific sandwich ELISAs, we determined the amounts of Abeta3(pE)-40 and Abeta3(pE)-42(43) in AD brain compared with other forms. This analysis showed that Abeta3(pE)-40 is closely correlated with the extent of Abeta deposition in blood vessels, whereas Abeta3(pE)-42(43) is not. In addition, Abeta3(pE)-42(43) is an important component of the Abeta deposited in senile plaques of the AD brain, constituting approximately 25% of the total Abeta42(43). In vitro comparison of Abeta1-42 and Abeta3(pE)-42 showed that Abeta3(pE)-42 is highly prone to oligomerization. These findings suggest that Abeta3(pE)-42 may be particularly important in AD pathogenesis.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Staining for pyroglutamate-3 Aβ revealed a sharp reduction in immunoreactivity in PLX5622-treated 5xFAD mice in the cortex.
“Staining for pyroglutamate-3 Aβ, which forms the plaque cores23, revealed a sharp reduction in immunoreactivity in PLX5622-treated 5xFAD mice in the cortex (Fig. 4p; Supplementary Figure 6G–H), along with reductions in 6E10+ diffuse plaques (Fig. 4o; Supplementary Figure 6G–H).”
From Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model (2019) · cites this paper as [23]
Cites
Glenner, G. G., & Wong, C. W. (1984) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(84)80190-4 · Cited by 5,404 · see citing works
The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor
Kang, J., Lemaire, H.-G., Unterbeck, A., Salbaum, J. M., Masters, C. L., Grzeschik, K.-H., Multhaup, G., Beyreuther, K., & Müller-Hill, B. (1987) · Nature · doi:10.1038/325733a0 · Cited by 4,619 · see citing works
Amyloid plaque core protein in Alzheimer disease and Down syndrome.
Masters, C. L., Simms, G., Weinman, N. A., Multhaup, G., McDonald, B. L., & Beyreuther, K. (1985) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.82.12.4245 · Cited by 4,431 · see citing works
Scheuner, D., Eckman, C., Jensen, M., Song, X., Citron, M., Suzuki, N., Bird, T. D., Hardy, J., Hutton, M., Kukull, W., et al. (1996) · Nature Medicine · doi:10.1038/nm0896-864 · Cited by 2,599 · see citing works
Self-citationDiagnosis of Alzheimer's Disease
Khachaturian, Z. S. (1985) · Archives of Neurology · doi:10.1001/archneur.1985.04060100083029 · Cited by 2,499 · see citing works
Jarrett, J. T., Berger, E. P., & Lansbury, P. T. (1993) · Biochemistry · doi:10.1021/bi00069a001 · Cited by 2,022 · see citing works
Iwatsubo, T., Odaka, A., Suzuki, N., Mizusawa, H., Nukina, N., & Ihara, Y. (1994) · Neuron · doi:10.1016/0896-6273(94)90458-8 · Cited by 1,774 · see citing works
Citron, M., Oltersdorf, T., Haass, C., McConlogue, L., Hung, A. Y., Seubert, P., Vigo-Pelfrey, C., Lieberburg, I., & Selkoe, D. J. (1992) · Nature · doi:10.1038/360672a0 · Cited by 1,757 · see citing works
Borchelt, D. R., Thinakaran, G., Eckman, C. B., Lee, M. K., Davenport, F., Ratovitsky, T., Prada, C.-M., Kim, G., Seekins, S., Yager, D., et al. (1996) · Neuron · doi:10.1016/s0896-6273(00)80230-5 · Cited by 1,478 · see citing works
Self-citationSuzuki, N., Cheung, T. T., Cai, X.-D., Odaka, A., Otvos, L., Eckman, C., Golde, T. E., & Younkin, S. G. (1994) · Science · doi:10.1126/science.8191290 · Cited by 1,471 · see citing works
Self-citationIncreased amyloid-β42(43) in brains of mice expressing mutant presenilin 1
Duff, K., Eckman, C., Zehr, C., Yu, X., Prada, C.-M., Pérez‐Tur, J., Hutton, M., Buée, L., Harigaya, Y., Yager, D., et al. (1996) · Nature · doi:10.1038/383710a0 · Cited by 1,453 · see citing works
Self-citationProduction of the Alzheimer Amyloid β Protein by Normal Proteolytic Processing
Shoji, M., Golde, T. E., Ghiso, J., Cheung, T. T., Estus, S., Shaffer, L. M., Cai, X.-D., McKay, D. M., Tintner, R., Frangione, B., et al. (1992) · Science · doi:10.1126/science.1439760 · Cited by 1,447 · see citing works
Self-citationCitron, M., Westaway, D., Xia, W., Carlson, G., Diehl, T., Levesque, G., Johnson-wood, K., Lee, M., Seubert, P., Davis, A., et al. (1997) · Nature Medicine · doi:10.1038/nm0197-67 · Cited by 1,271 · see citing works
Release of Excess Amyloid β Protein from a Mutant Amyloid β Protein Precursor
Cai, X.-D., Golde, T. E., & Younkin, S. G. (1993) · Science · doi:10.1126/science.8424174 · Cited by 913 · see citing works
Self-citationRoher, A. E., Lowenson, J. D., Clarke, S., Wolkow, C., Wang, R., Cotter, R. J., Reardon, I. M., Zürcher-Neely, H. A., Heinrikson, R. L., & Ball, M. J. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)53661-9 · Cited by 799 · see citing works
Amyloid β Protein (Aβ) in Alzheimeri's Disease Brain
Gravina, S. A., Ho, L., Eckman, C. B., Long, K. E., Otvos, L., Younkin, L. H., Suzuki, N., & Younkin, S. G. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.13.7013 · Cited by 676 · see citing works
Self-citationSaido, T. C., Iwatsubo, T., Mann, D. M. A., Shimada, H., Ihara, Y., & Kawashima, S. (1995) · Neuron · doi:10.1016/0896-6273(95)90301-1 · Cited by 587 · see citing works
Self-citationMass spectrometry of purified amyloid beta protein in Alzheimer's disease.
Mori, H., Takio, K., OGAWARA, M., & Selkoe, D. J. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)41896-0 · Cited by 481 · see citing works
Mann, D. M. A., & Esiri, M. M. (1989) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(89)90019-1 · Cited by 471 · see citing works
Neuritic plaques and cerebrovascular amyloid in Alzheimer disease are antigenically related.
Wong, C. W., Quaranta, V., & Glenner, G. G. (1985) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.82.24.8729 · Cited by 438 · see citing works
Amyloid β protein (Aβ) deposition: Aβ42(43) precedes Aβ40 in down Syndrome
Iwatsubo, T., Mann, D. M. A., Odaka, A., Suzuki, N., & Ihara, Y. (1995) · Annals of Neurology · doi:10.1002/ana.410370305 · Cited by 380 · see citing works
Amino-terminal Deletions Enhance Aggregation of β-Amyloid Peptides in Vitro
Pike, C. J., Overman, M. J., & Cotman, C. W. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.41.23895 · Cited by 302 · see citing works
Amino- and carboxyl-terminal heterogeneity of β-amyloid peptides deposited in human brain
Saido, T. C., Yamao-Harigaya, W., Iwatsubo, T., & Kawashima, S. (1996) · Neuroscience Letters · doi:10.1016/0304-3940(96)12970-0 · Cited by 270 · see citing works
Self-citationIwatsubo, T., Saido, T. C., Mann, D. M. A., Lee, V. M.-Y., & Trojanowski, J. Q. (1996) · Europe PMC (PubMed Central) · Cited by 248 · see citing works
Self-citationHigh tissue content of soluble beta 1-40 is linked to cerebral amyloid angiopathy.
Suzuki, N., Iwatsubo, T., Odaka, A., Ishibashi, Y., Kitada, C., & Ihara, Y. (1994) · PubMed Central · Cited by 206 · see citing works
Neuritic Plaque Amyloid in Alzheimer's Disease Is Highly Racemized
Shapira, R., Austin, G. E., & Mirra, S. S. (1988) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1988.tb13231.x · Cited by 184 · see citing works
Tamaoka, A., Odaka, A., Ishibashi, Y., Usami, M., Sahara, N., Suzuki, N., Nukina, N., Mizusawa, H., Shoji, S., & Kanazawa, I. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(20)30050-8 · Cited by 165 · see citing works
Spatial resolution of the primary beta-amyloidogenic process induced in postischemic hippocampus.
Saido, T. C., Yokota, M., Maruyama, K., Yamao‐Harigaya, W., Tani, E., Ihara, Y., & Kawashima, S. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)36599-7 · Cited by 80 · see citing works
Self-citationQuantification of Modified Amyloid β Peptides in Alzheimer Disease and Down Syndrome Brains
Hosoda, R., Saido, T. C., Otvos, L., Arai, T., Mann, D. M. A., Lee, V. M.-Y., Trojanowski, J. Q., & Iwatsubo, T. (1998) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/00005072-199811000-00012 · Cited by 79 · see citing works
Self-citationHarigaya, Y., Shoji, M., Kawarabayashi, T., Kanai, M., Nakamura, T., Iizuka, T., Igeta, Y., Saido, T. C., Sahara, N., Mori, H., et al. (1995) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1995.1912 · Cited by 46 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Classification and basic pathology of Alzheimer disease
Duyckaerts, C., Delatour, B., & Potier, M.-C. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0532-1 · Cited by 1,031 · see citing works
Cerebral amyloid angiopathy and Alzheimer disease — one peptide, two pathways
Greenberg, S. M., Bacskai, B. J., Hernandez-Guillamon, M., Pruzin, J., Sperling, R., & van Veluw, S. J. (2020) · Nature Reviews Neurology · doi:10.1038/s41582-019-0281-2 · Cited by 947 · see citing works
Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease
Ikonomovic, M. D., Klunk, W. E., Abrahamson, E. E., Mathis, C. A., Price, J. C., Tsopelas, N. D., Lopresti, B. J., Ziolko, S., Bi, W., Paljug, W. R., et al. (2008) · Brain · doi:10.1093/brain/awn016 · Cited by 933 · see citing works
Spangenberg, E., Severson, P. L., Hohsfield, L. A., Crapser, J., Zhang, J., Burton, E. A., Zhang, Y., Spevak, W., Lin, J., Phan, N. Y., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11674-z · Cited by 939 · see citing works
TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques
Wang, Y., Ulland, T. K., Ulrich, J. D., Song, W., Tzaferis, J. A., Hole, J. T., Yuan, P., Mahan, T. E., Shi, Y., Gilfillan, S., et al. (2016) · Journal of Experimental Medicine · doi:10.1084/jem.20151948 · Cited by 840 · see citing works
Alzheimer's Disease: From Pathology to Therapeutic Approaches
Jakob‐Roetne, R., & Jacobsen, H. (2009) · Angewandte Chemie International Edition · doi:10.1002/anie.200802808 · Cited by 626 · see citing works
Casas, C., Sergeant, N., Itier, J.-M., Blanchard, V., Wirths, O., van der Kolk, N., Vingtdeux, V., van de Steeg, E., Ret, G., Canton, T., et al. (2004) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)63388-3 · Cited by 400 · see citing works
Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease
Gouras, G. K., Tampellini, D., Takahashi, R. H., & Capetillo-Zarate, E. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0679-9 · Cited by 372 · see citing works
Portelius, E., Bogdanovic, N., Gustavsson, M. K., Volkmann, I., Brinkmalm, G., Zetterberg, H., Winblad, B., & Blennow, K. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0690-1 · Cited by 348 · see citing works
On the Seeding and Oligomerization of pGlu-Amyloid Peptides (<i>in vitro</i>)
Schilling, S., Lauber, T., Schaupp, M., Manhart, S., Scheel, E., Böhm, G., & Demuth, H.-U. (2006) · Biochemistry · doi:10.1021/bi0612667 · Cited by 254 · see citing works
Kitazawa, M., Medeiros, R., & M. LaFerla, F. (2012) · Current Pharmaceutical Design · doi:10.2174/138161212799315786 · Cited by 178 · see citing works
Wirths, O., Breyhan, H., Cynis, H., Schilling, S., Demuth, H.-U., & Bayer, T. A. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0557-5 · Cited by 174 · see citing works
Bouter, Y., Dietrich, K., Wittnam, J. L., Rezaei-Ghaleh, N., Pillot, T., Papot-Couturier, S., Lefebvre, T., Sprenger, F., Wirths, O., Zweckstetter, M., et al. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1129-2 · Cited by 175 · see citing works
Pyroglutamate Abeta pathology in APP/PS1KI mice, sporadic and familial Alzheimer’s disease cases
Wirths, O., Bethge, T., Marcello, A., Harmeier, A., Jawhar, S., Lucassen, P. J., Multhaup, G., Brody, D. L., Esparza, T., Ingelsson, M., et al. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-009-0314-x · Cited by 106 · see citing works
Meißner, J. N., Bouter, Y., & Bayer, T. A. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-142868 · Cited by 16 · see citing works
- Authors
- Harigaya, Y., Saido, T. C., Eckman, C. B., Prada, C.-M., Shoji, M., & Younkin, S. G.
- Affiliations
- Mayo Clinic (US)
- RIKEN Center for Brain Science (JP)
- Gunma University (JP)
- Corresponding author
- Harigaya, Yasuo
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2000-09
- Volume
- 276
- Issue
- 2
- Pages
- 422-427
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2027693753
- Cited by
- 202
- References
- 30
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 7 · 2023: 11 · 2022: 5 · 2021: 15 · 2020: 10 · 2019: 11 · 2018: 7 · 2017: 15 · 2016: 8 · 2015: 7 · 2014: 11 · 2013: 9 · 2012: 14
- FWCI
- 0.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Univers Foundation
- Ministry of Education, Culture, Sports, Science and Technology (10832002, 10832003)
- Ministry of Health, Labour and Welfare
- MSD Life Science Foundation, Public Interest Incorporated Foundation
- Uehara Memorial Foundation
- Topics
- Health Sciences › Medicine › Physiology › 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, Alzheimer's disease, amyloid deposits, amyloid plaques, amyloid-beta 42, Aβ40, oligomerization, amyloid deposition, Alzheimer's disease pathogenesis
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Brain, Female, Humans, Male, Peptide Fragments, Pyrrolidonecarboxylic Acid, Amyloid beta-Peptides, Plaque, Amyloid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review