NDLI: Alzheimer β-Amyloid Homodimers Facilitate Aβ Fibrillization and the Generation of Conformational Antibodies

Content Provider	Journal of Biological Chemistry (JBC)
Author	Schmechel, Ariane Zentgraf, Hanswalter Scheuermann, Stefan Fritz, Guenter Pipkorn, Rüdiger Reed, Jennifer Beyreuther, Konrad Bayer, Thomas A. Multhaup, Gerd
Abstract	We reported previously that stabilized β-amyloid peptide dimers were derived from mutant amyloid precursor protein with a single cysteine in the ectodomain juxtamembrane position. In vivo studies revealed that two forms of SDS-stable Aβ homodimers exist, species ending at Aβ40 and Aβ42. The phenomenon of the transformation of the initially deposited 42-residue β-amyloid peptide into the amyloid fibrils of Alzheimer`s disease plaques remains to be explained in physical terms, i.e. energetically and structurally. We therefore performed spectroscopic analyses revealing that engineered dimeric peptides ending at residue 42 displayed a much more pronounced β-structural transition than corresponding monomers. Specifically, the single chemically induced dimerization of Aβ peptides significantly increased the β-sheet content by a factor of 2. The C-terminal residues Ile-41 and Ala-42 of dimeric forms further increased the β-sheet content by roughly one-third. In contrast to Aβ42, the β-sheet content of the α- and γ-secretase-generated p3 fragments did not necessarily correlate with the tendency to form fibrils, although p3/17–42 had a pronounced thread forming character with fibril lengths of up to 2.5 μm. Electron microscopic images show that forms of p3/17–42 generated smaller granular particles than forms ending at residue 40. We discuss these findings in terms of Aβ1–42 dimers representing paranuclei, which self-aggregate into ribbon-like ordered fibrils by elongation. Based on Aβ42 dimer-specific titers of a polyclonal antiserum we propose that the Aβ homodimer represents a nidus for plaque formation and a well defined novel therapeutic target.
Related Links	http://www.jbc.org/content/278/37/35317.abstract
Ending Page	35324
Starting Page	35317
Page Count	8
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	37
Volume Number	278
DOI	10.1074/jbc.M303547200
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2003-09-12
Access Restriction	Open
Subject Keyword	Protein Structure and Folding
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

Soluble Prion Protein Inhibits Amyloid-β (Aβ) Fibrillization and Toxicity

Accelerating Amyloid-β Fibrillization Reduces Oligomer Levels and Functional Deficits in Alzheimer Disease Mouse Models

Discovery and Structure Activity Relationship of Small Molecule Inhibitors of Toxic β-Amyloid-42 Fibril Formation

Isolation and Characterization of Patient-derived, Toxic, High Mass Amyloid β-Protein (Aβ) Assembly from Alzheimer Disease Brains

Atomic-resolution map of the interactions between an amyloid inhibitor protein and amyloid β (Aβ) peptides in the monomer and protofibril states

Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis

Temporal Profile of Amyloid-β (Aβ) Oligomerization in an in Vivo Model of Alzheimer Disease A LINK BETWEEN Aβ AND TAU PATHOLOGY

Conformational Differences between Two Amyloid β Oligomers of Similar Size and Dissimilar Toxicity

A Novel Inhibitor of Amyloid β (Aβ) Peptide Aggregation FROM HIGH THROUGHPUT SCREENING TO EFFICACY IN AN ANIMAL MODEL OF ALZHEIMER DISEASE

Alzheimer β-Amyloid Homodimers Facilitate Aβ Fibrillization and the Generation of Conformational Antibodies

Similar Documents

Soluble Prion Protein Inhibits Amyloid-β (Aβ) Fibrillization and Toxicity

Accelerating Amyloid-β Fibrillization Reduces Oligomer Levels and Functional Deficits in Alzheimer Disease Mouse Models

Discovery and Structure Activity Relationship of Small Molecule Inhibitors of Toxic β-Amyloid-42 Fibril Formation

Isolation and Characterization of Patient-derived, Toxic, High Mass Amyloid β-Protein (Aβ) Assembly from Alzheimer Disease Brains

Atomic-resolution map of the interactions between an amyloid inhibitor protein and amyloid β (Aβ) peptides in the monomer and protofibril states

Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis

Temporal Profile of Amyloid-β (Aβ) Oligomerization in an in Vivo Model of Alzheimer Disease A LINK BETWEEN Aβ AND TAU PATHOLOGY

Conformational Differences between Two Amyloid β Oligomers of Similar Size and Dissimilar Toxicity

A Novel Inhibitor of Amyloid β (Aβ) Peptide Aggregation FROM HIGH THROUGHPUT SCREENING TO EFFICACY IN AN ANIMAL MODEL OF ALZHEIMER DISEASE

Alzheimer β-Amyloid Homodimers Facilitate Aβ Fibrillization and the Generation of Conformational Antibodies