-
[show abstract]
[hide abstract]
ABSTRACT: We reported previously that stabilized beta-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 A beta homodimers exist, species ending at A beta 40 and A beta 42. The phenomenon of the transformation of the initially deposited 42-residue beta-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 beta-structural transition than corresponding monomers. Specifically, the single chemically induced dimerization of A beta peptides significantly increased the beta-sheet content by a factor of 2. The C-terminal residues Ile-41 and Ala-42 of dimeric forms further increased the beta-sheet content by roughly one-third. In contrast to A beta 42, the beta-sheet content of the alpha- and gamma-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 microM. 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 A beta 1-42 dimers representing paranuclei, which self-aggregate into ribbon-like ordered fibrils by elongation. Based on A beta 42 dimer-specific titers of a polyclonal antiserum we propose that the A beta homodimer represents a nidus for plaque formation and a well defined novel therapeutic target.
Journal of Biological Chemistry 10/2003; 278(37):35317-24. · 4.77 Impact Factor
-
[show abstract]
[hide abstract]
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.
Journal of Biological Chemistry 09/2003; 278(37):35317-35324. · 4.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Oxidative stress was presented to play an important role in the pathogenesis of Alzheimer's disease (AD), especially in the early evolution of AD amyloidogenesis and not only as a consequence thereof. The effect of oxidative stress catalysed by transition metals appears to have a critical relevance in AD. Metal-ion homeostasis is severely dysregulated in AD and it was found that experimentally induced disturbances in the homeostasis of Zn(II) and Cu(II) affect the amyloid precursor protein (APP) metabolism. APP itself binds Zn(II) and Cu(II) at nanomolar concentrations and an altered APP metabolism or expression level is believed to result in neurotoxic processes.
Free Radical Biology and Medicine 08/2002; 33(1):45-51. · 5.42 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We reported previously that the carbohydrate domain of the amyloid precursor protein is involved in amyloid precursor protein
(APP)-APP interactions. Functional in vitro studies suggested that this interaction occurs through the collagen binding site of APP. The physiological significance remained
unknown, because it is not understood whether and how APP dimerization occurs in vivo. Here we report that cellular APP exists as homodimers matching best with a two-site model. Consistent with our published
crystallographic data, we show that a deletion of the entire sequence after the kunitz protease inhibitor domain did not abolish
APP homodimerization, suggesting that two domains are critically involved but that neither is essential for homodimerization.
Finally, we generated stabilized dimers by expressing mutant APP with a single cysteine in the ectodomain juxtamembrane region.
Mutation of Lys624 to cysteine produced ∼6–8-fold more Aβ than cells expressing normal APP. Our results suggest that amyloid Aβ production can
in principle be positively regulated by dimerizationin vivo. We suggest that dimerization could be a physiologically important mechanism for regulating the proposed signal activity
of APP.
Journal of Biological Chemistry 09/2001; 276(36):33923-33929. · 4.77 Impact Factor
