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| STRUCTURAL ALTERATIONS IN THE PEPTIDE BACKBONE OF BETA-AMYLOID CORE PROTEIN MAY ACCOUNT FOR ITS DEPOSITION AND STABILITY IN ALZHEIMERS-DISEASE |
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| Author(s): ROHER AE, LOWENSON JD, CLARKE S, WOLKOW C, WANG R, COTTER RJ, REARDON IM, ZURCHERNEELY HA, HEINRIKSON RL, BALL MJ, GREENBERG BD |
| Source: JOURNAL OF BIOLOGICAL CHEMISTRY Volume: 268 Issue: 5 Pages: 3072-3083 Published: FEB 15 1993 |
| Times Cited: 432 References: 81 |
| Abstract: The structure of beta-amyloid (betaA) 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 betaA 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 betaA has a maximal length of 42 residues, but shorter forms with ''ragged'' NH2 termini are also present. Tryptic peptide analysis revealed heterogeneity in the betaA1-5 and betaA6-16 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 betaA 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. BetaA purified from the leptomeningeal microvasculature contains the same structural alterations as parenchymal, betaA, but is 2 residues shorter at its COOH terminus. Using two different purification protocols, and using a synthetic betaA1-42 peptide as a control, we show that these modifications arose endogenously and were not caused by the experimental manipulations. The abundance of structurally altered aspartyl residues may profoundly affect the conformation of the betaA protein within plaque cores and thus significantly impact normal catabolic processes designed to limit its deposition. These alterations may therefore contribute to the production and stability of beta-amyloid deposits in Alzheimer brain tissue. |
| Document Type: Article |
| Language: English |
| Reprint Address: ROHER, AE (reprint author), WAYNE STATE UNIV, SCH MED, DEPT ANAT & CELL BIOL, 540 E CANFIELD AVE, DETROIT, MI 48201 USA |
Addresses:
1. UCLA LOS ANGELES, DEPT CHEM & BIOCHEM, LOS ANGELES, CA 90024 USA
2. UCLA LOS ANGELES, INST MOLEC BIOL, LOS ANGELES, CA 90024 USA
3. JOHNS HOPKINS UNIV, SCH MED, DEPT PHARMACOL & MOLEC SCI, MIDDLE ATLANTIC MASS SPECTROMETRY LAB, BALTIMORE, MD 21205 USA
4. UPJOHN CO, LABS, CNS RES, KALAMAZOO, MI 49001 USA
5. OREGON HLTH SCI UNIV, DEPT PATHOL, PORTLAND, OR 97201 USA
6. OREGON HLTH SCI UNIV, DEPT NEUROL, PORTLAND, OR 97201 USA |
| Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 |
| Subject Category: Biochemistry & Molecular Biology |
| IDS Number: KM161 |
| ISSN: 0021-9258 |
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