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High sensitivity analysis of amyloid-beta peptide composition in amyloid deposits from human and PS2APP mouse brain.
Neuroscience 2006; 143(2):461-75N

Abstract

Cortical amyloid-beta (Abeta) deposition is considered essential in Alzheimer's disease (AD) and is also detectable in nondemented individuals with pathologic aging (PA). The present work presents a detailed analysis of the Abeta composition in various plaque types from human AD and PA cases, compared with plaque Abeta isolated from PS2APP mice. To determine minute amounts of Abeta from 30 to 50 laser-dissected amyloid deposits, we used a highly sensitive mass spectrometry procedure after restriction protease lysyl endopeptidase (Lys-C) digestion. This approach allowed the analysis of the amino-terminus and, including a novel ionization modifier, for the first time the carboxy-terminus of Abeta at a detection limit of approximately 200 fmol. In addition, full length Abeta 40/42 and pyroglutamate 3-42 were analyzed using a highly sensitive urea-based Western blot procedure. Generally, Abeta fragments were less accessible in human deposits, indicative of more posttranslational modifications. Thioflavine S positive cored plaques in AD were found to contain predominantly Abeta 42, whereas thioflavine S positive compact plaques and vascular amyloid consist mostly of Abeta 40. Diffuse plaques from AD and PA, as well as from PS2APP mice are composed predominantly of Abeta 1-42. Despite biochemical similarities in human and PS2APP mice, immuno-electron microscopy revealed an extensive extracellular matrix associated with Abeta fibrils in AD, specifically in diffuse plaques. Amino-terminal truncations of Abeta, especially pyroglutamate 3-40/42, are more frequently found in human plaques. In cored plaques we measured an increase of N-terminal truncations of approximately 20% between Braak stages IV to VI. In contrast, diffuse plaques of AD and PA cases, show consistently only low levels of amino-terminal truncations. Our data support the concept that diffuse plaques represent initial Abeta deposits but indicate a structural difference for Abeta depositions in human AD compared with PS2APP mice already at the stage of diffuse plaque formation.

Authors+Show Affiliations

Pharma Research Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.No affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

17008022

Citation

Güntert, A, et al. "High Sensitivity Analysis of Amyloid-beta Peptide Composition in Amyloid Deposits From Human and PS2APP Mouse Brain." Neuroscience, vol. 143, no. 2, 2006, pp. 461-75.
Güntert A, Döbeli H, Bohrmann B. High sensitivity analysis of amyloid-beta peptide composition in amyloid deposits from human and PS2APP mouse brain. Neuroscience. 2006;143(2):461-75.
Güntert, A., Döbeli, H., & Bohrmann, B. (2006). High sensitivity analysis of amyloid-beta peptide composition in amyloid deposits from human and PS2APP mouse brain. Neuroscience, 143(2), pp. 461-75.
Güntert A, Döbeli H, Bohrmann B. High Sensitivity Analysis of Amyloid-beta Peptide Composition in Amyloid Deposits From Human and PS2APP Mouse Brain. Neuroscience. 2006 Dec 1;143(2):461-75. PubMed PMID: 17008022.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - High sensitivity analysis of amyloid-beta peptide composition in amyloid deposits from human and PS2APP mouse brain. AU - Güntert,A, AU - Döbeli,H, AU - Bohrmann,B, Y1 - 2006/09/27/ PY - 2006/05/03/received PY - 2006/07/27/revised PY - 2006/08/07/accepted PY - 2006/9/30/pubmed PY - 2007/1/27/medline PY - 2006/9/30/entrez SP - 461 EP - 75 JF - Neuroscience JO - Neuroscience VL - 143 IS - 2 N2 - Cortical amyloid-beta (Abeta) deposition is considered essential in Alzheimer's disease (AD) and is also detectable in nondemented individuals with pathologic aging (PA). The present work presents a detailed analysis of the Abeta composition in various plaque types from human AD and PA cases, compared with plaque Abeta isolated from PS2APP mice. To determine minute amounts of Abeta from 30 to 50 laser-dissected amyloid deposits, we used a highly sensitive mass spectrometry procedure after restriction protease lysyl endopeptidase (Lys-C) digestion. This approach allowed the analysis of the amino-terminus and, including a novel ionization modifier, for the first time the carboxy-terminus of Abeta at a detection limit of approximately 200 fmol. In addition, full length Abeta 40/42 and pyroglutamate 3-42 were analyzed using a highly sensitive urea-based Western blot procedure. Generally, Abeta fragments were less accessible in human deposits, indicative of more posttranslational modifications. Thioflavine S positive cored plaques in AD were found to contain predominantly Abeta 42, whereas thioflavine S positive compact plaques and vascular amyloid consist mostly of Abeta 40. Diffuse plaques from AD and PA, as well as from PS2APP mice are composed predominantly of Abeta 1-42. Despite biochemical similarities in human and PS2APP mice, immuno-electron microscopy revealed an extensive extracellular matrix associated with Abeta fibrils in AD, specifically in diffuse plaques. Amino-terminal truncations of Abeta, especially pyroglutamate 3-40/42, are more frequently found in human plaques. In cored plaques we measured an increase of N-terminal truncations of approximately 20% between Braak stages IV to VI. In contrast, diffuse plaques of AD and PA cases, show consistently only low levels of amino-terminal truncations. Our data support the concept that diffuse plaques represent initial Abeta deposits but indicate a structural difference for Abeta depositions in human AD compared with PS2APP mice already at the stage of diffuse plaque formation. SN - 0306-4522 UR - https://www.unboundmedicine.com/medline/citation/17008022/High_sensitivity_analysis_of_amyloid_beta_peptide_composition_in_amyloid_deposits_from_human_and_PS2APP_mouse_brain_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(06)01083-9 DB - PRIME DP - Unbound Medicine ER -