Structural alterations in the peptide backbone of beta-amyloid core protein may account for its deposition and stability in Alzheimer's disease.

Roher, 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.

doi:10.1016/s0021-9258(18)53661-9

Cited by 799Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Structural alterations in the peptide backbone of beta-amyloid core protein may account for its deposition and stability in Alzheimer's disease.

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Roher, A.E., Lowenson, J.D., Clarke, S., Wolkow, C., Wang, R., Cotter, R.J., Reardon, I.M., Zürcher-Neely, H.A. +2 more·1993·Journal of Biological Chemistry

DOI 10.1016/s0021-9258(18)53661-9

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Abstract

The structure of beta-amyloid (beta A) from Alzheimer disease brains was examined to determine if post-translational modifications might be linked to the abnormal deposition of this peptide in the diseased tissue. The beta A peptides were isolated from the compact amyloid cores of neuritic plaques and separated from minor glycoprotein components by size-exclusion high-pressure liquid chromatography (HPLC). This parenchymal beta A has a maximal length of 42 residues, but shorter forms with "ragged" NH2 termini are also present. Tryptic peptide analysis revealed heterogeneity in the beta A1-5 and beta A6-16 peptides, each of which eluted as four peaks on reverse phase HPLC. Amino acid composition and sequence analyses, mass spectrometry, enzymatic methylation, and stereoisomer determinations revealed that these multiple peptide forms resulted from structural rearrangements of the aspartyl residues at beta A positions 1 and 7. The L-isoaspartyl form predominates at each of these positions, whereas the D-isoaspartyl, L-aspartyl, and D-aspartyl forms are present in lesser amounts. beta A purified from the leptomeningeal microvasculature contains the same structural alterations as parenchymal beta A, but is 2 residues shorter at its COOH terminus. Using two different purification protocols, and using a synthetic beta A1-42 peptide as a control, we show that these modifications arose endogenously and were not caused by the experimental manipulations. The abundance of structurally al…

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This finding is consistent with previous reports that most of the Aβ in AD brains is amino-terminally truncated or modified.
“Th is finding is consistent with pr evious re ports (15,17,18) that most of the A{3 in AD brains is amino-ter mi na lly trunca te d or modifi ed.”
From Amyloid β Protein (Aβ) in Alzheimeri's Disease Brain (1995) · cites this paper as [15]
The increased amount of Aβ detected with 4G8 suggests that there may be considerable amino-terminally truncated Aβ in AD brain.
“The increased amount of A{3 detected with 4G8 suggests that there may be considerable amino-terminally truncated A{3 in AD brain, consistent with the results of others who have examined the SDSinsoluble A{3 in AD brain (1S, 17,18).”
From Amyloid β Protein (Aβ) in Alzheimeri's Disease Brain (1995) · cites this paper as [15]
SDS-insoluble amyloid in senile plaque cores is primarily Aβ1-42.
“Recent reports using this approach, particularly those of Roher and his colleagues, indicate that the SDS-insoluble amyloid in senile plaque cores is primarily A(31-42 (15,17)”
From Amyloid β Protein (Aβ) in Alzheimeri's Disease Brain (1995) · cites this paper as [15]
Much of the Aβ deposited as amyloid in AD brain is resistant to SDS extraction and requires formic acid for solubilization.
“It is well established that much of the A␤ deposited as amyloid in AD brain is resistant to SDS extraction and requires formic acid for solubilization (Roher et al., 1993).”
From Age-Dependent Changes in Brain, CSF, and Plasma Amyloid β Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease (2001) · cites this paper as Roher et al., 1993

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Authors: Roher, 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.
Affiliations: Wayne State University (US)
ORCID: Lowenson, J.D.
Clarke, S.
Cotter, R.J.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 1993-02
Volume: 268
Issue: 5
Pages: 3072-3083
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1016/s0021-9258(18)53661-9
OpenAlex: W2108689038
Cited by: 799
References: 0
Citations by year: 2026: 9 · 2025: 24 · 2024: 12 · 2023: 15 · 2022: 16 · 2021: 19 · 2020: 24 · 2019: 22 · 2018: 21 · 2017: 23 · 2016: 23 · 2015: 21 · 2014: 24 · 2013: 21 · 2012: 22
FWCI: 26.21
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 10118 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: National Institute on Aging (P30 AG 08017, P30AG008017)
National Institute of General Medical Sciences (GM 26020)
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, neuritic plaques, post-translational modification, amyloid deposition, peptide conformation
MeSH terms: Alzheimer Disease, Amino Acid Sequence, Aspartic Acid, Brain, Brain Chemistry, Centrifugation, Density Gradient, Cerebrovascular Circulation, Chromatography, Gel, Chromatography, High Pressure Liquid, Cyanogen Bromide, Humans, Meninges, Molecular Sequence Data, Muscle, Smooth, Vascular, Peptide Fragments, Peptides, Protein Processing, Post-Translational, Ultracentrifugation, Amyloid beta-Peptides

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Structural alterations in the peptide backbone of beta-amyloid core protein may account for its deposition and stability in Alzheimer's disease.

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