Anti-Abeta1 11 Antibody Binds to Different beta-Amyloid Species, Inhibits Fibril Formation, and Disaggregates Preformed Fibrils but Not the Most Toxic Oligomers (original) (raw)

Anti-Aβ1–11 Antibody Binds to Different β-Amyloid Species, Inhibits Fibril Formation, and Disaggregates Preformed Fibrils but Not the Most Toxic Oligomers

Journal of Biological Chemistry, 2007

Different strategies proposed as therapy for Alzheimer disease (AD) have aimed to reduce the level of toxic forms of A␤ peptide in the brain. Here, we directly analyze the therapeutic utility of the polyclonal anti-A␤ 1-11 antibody induced in 3xTg-AD mice vaccinated with the second generation prototype epitope vaccine. Substoichiometric concentrations of purified anti-A␤ 1-11 antibody prevented aggregation of A␤ 42 and induced disaggregation of preformed A␤ 42 fibrils down to nonfilamentous and nontoxic species. Anti-A␤ 1-11 antibody delayed A␤ 42 oligomer formation but ultimately appeared to stabilize nonfibrillar conformations, including oligomer-like assemblies. The reduced oligomer-mediated cytotoxicity observed upon preincubation of A␤ oligomers with the anti-A␤ 1-11 antibody in the absence of oligomer disaggregation suggests a possible oligomer rearrangement in the presence of the antibody. These in vitro observations suggest that preventive vaccination may protect from AD or may delay the onset of the disease, whereas therapeutic vaccination cannot disrupt the toxic oligomers and may only minimally alleviate preexisting AD pathology. * This work was supported by National Institutes of Health R01 Grants AG20241 and NS50895 (to D. H. C. and M. G. A.) and NS3I230 (to C. G. C.) and Alzheimer's Association Grant IIRG-03-6279 (to M. G. A. and D. H. C.

Structural conversion of neurotoxic amyloid-β1–42 oligomers to fibrils

Nature Structural & Molecular Biology, 2010

The Aβ42 peptide rapidly aggregates to form oligomers, protofibils and fibrils en route to the deposition of amyloid plaques associated with Alzheimer's disease. We show that low temperature and low salt can stabilize disc-shaped oligomers (pentamers) that are significantly more toxic to murine cortical neurons than protofibrils and fibrils. We find that these neurotoxic oligomers do not have the β-sheet structure characteristic of fibrils. Rather, the oligomers are composed of loosely aggregated strands whose C-terminus is protected from solvent exchange and which have a turn conformation placing Phe19 in contact with Leu34. On the basis of NMR spectroscopy, we show that the structural conversion of Aβ42 oligomers to fibrils involves the association of these loosely aggregated strands into β-sheets whose individual β-strands polymerize in a parallel, inregister orientation and are staggered at an inter-monomer contact between Gln15 and Gly37. A major pathological hallmark of Alzheimer's disease (AD) is the formation of neuritic plaques within the gray matter of AD patients 1. These plaques are composed primarily of filamentous aggregates (fibrils) of the 39-42 amino acid long amyloid-β (Aβ) peptide formed from the proteolytic cleavage of the amyloid precursor protein by βand γ-secretases 2-5. The major species of Aβ production are the Aβ40 and Aβ42 peptides, with Aβ42 being predominant in neuritic plaques of AD patients and exhibiting a higher in vitro propensity to Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Studies on the in Vitro Assembly of Aβ 1–40: Implications for the Search for Aβ Fibril Formation Inhibitors

Journal of Structural Biology, 2000

The progressive deposition of the amyloid β peptide (Aβ) in fibrillar form is a key feature in the development of the pathology in Alzheimer's disease (AD). We have characterized the time course of Aβ fibril formation using a variety of assays and under different experimental conditions. We describe in detail the morphological development of the Aβ polymerization process from pseudo-spherical

A Mini Review on Aβ Oligomers and its Pathogencity

Journal of the Chosun Natural Science, 2014

Amyloid oligomers are believed to play important causal roles in many types of amyloid-related degenerative diseases. Many different laboratories have reported amyloid oligomers that differ in size, morphology, toxicity, and method of preparation or purification, raising the question of the structural relationships among these oligomer preparations. The structural plasticity that has been reported to occur in amyloid formed from the same protein sequence indicates that it is quite possible that different oligomer preparations may represent distinct structural variants. In view of the difficulty in determining the precise structure of amyloids, conformation-and epitope-specific antibodies may provide a facile means of classifying amyloid oligomer structures. Conformation-dependent antibodies that recognize generic epitopes that are specifically associated with distinct aggregation states of many different amyloid-forming sequences indicate that there are at least two fundamentally distinct types of amyloid oligomers: fibrillar and prefibrillar oligomers. Classification of amyloid oligomers according to their underlying structures may be a more useful and rational approach than relying on differences in size and morphology.

Oligomeric and fibrillar species of amyloid-β peptides differentially affect neuronal viability

Journal of Biological …, 2002

Genetic evidence predicts a causative role for amyloid-␤ (A␤) in Alzheimer's disease. Recent debate has focused on whether fibrils (amyloid) or soluble oligomers of A␤ are the active species that contribute to neurodegeneration and dementia. We developed two aggregation protocols for the consistent production of stable oligomeric or fibrillar preparations of A␤-(1-42). Here we report that oligomers inhibit neuronal viability 10-fold more than fibrils and ϳ40-fold more than unaggregated peptide, with oligomeric A␤-(1-42)-induced inhibition significant at 10 nM. Under A␤-(1-42) oligomer-and fibril-forming conditions, A␤-(1-40) remains predominantly as unassembled monomer and had significantly less effect on neuronal viability than preparations of A␤-(1-42). We applied the aggregation protocols developed for wild type A␤-(1-42) to A␤-(1-42) with the Dutch (E22Q) or Arctic (E22G) mutations. Oligomeric preparations of the mutations exhibited extensive protofibril and fibril formation, respectively, but were not consistently different from wild type A␤-(1-42) in terms of inhibition of neuronal viability. However, fibrillar preparations of the mutants appeared larger and induced significantly more inhibition of neuronal viability than wild type A␤-(1-42) fibril preparations. These data demonstrate that protocols developed to produce oligomeric and fibrillar A␤-(1-42) are useful in distinguishing the structural and functional differences between A␤-(1-42) and A␤-(1-40) and genetic mutations of A␤-(1-42). Amyloid-␤ (A␤) 1 is derived by the proteolytic processing of amyloid precursor protein (APP), resulting in a peptide predominantly 40 or 42 amino acids in length. Mutations in APP and the presenilins that increase the amount of A␤-(1-42) cause AD (for review, see Ref. 1). Historically, the "amyloid

Physicochemical characteristics of soluble oligomeric Aβand their pathologic role in Alzheimer's disease

Neurological Research, 2005

AN OVERVIEW Alzheimer's disease (AD) neuropathology is characterized by the extracellular deposition of fibrillar amyloid in cortical senile plaques and in the walls of leptomeningeal and parenchymal arteries. These amyloid fibrils form when 40 and 42 amino acid residue Ab peptides, derived from a larger type I transmembrane molecule amyloid precursor protein (AbPP), polymerize. When released from AbPP by the action of the band c-secretases into the cytosolic or extracellular milieu, the Ab peptides generate transient metastable and disordered secondary structures due to the interaction of the hydrophobic domains with the surrounding