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Crystal structure of the amyloid-? p3 fragment provides a model for oligomer formation in Alzheimer's disease.

ABSTRACT: Alzheimer's disease is a progressive neurodegenerative disorder associated with the presence of amyloid-? (A?) peptide fibrillar plaques in the brain. However, current evidence suggests that soluble nonfibrillar A? oligomers may be the major drivers of A?-mediated synaptic dysfunction. Structural information on these A? species has been very limited because of their noncrystalline and unstable nature. Here, we describe a crystal structure of amylogenic residues 18-41 of the A? peptide (equivalent to the p3 ?/?-secretase fragment of amyloid precursor protein) presented within the CDR3 loop region of a shark Ig new antigen receptor (IgNAR) single variable domain antibody. The predominant oligomeric species is a tightly associated A? dimer, with paired dimers forming a tetramer in the crystal caged within four IgNAR domains, preventing uncontrolled amyloid formation. Our structure correlates with independently observed features of small nonfibrillar A? oligomers and reveals conserved elements consistent with residues and motifs predicted as critical in A? folding and oligomerization, thus potentially providing a model system for nonfibrillar oligomer formation in Alzheimer's disease.

SUBMITTER: Streltsov VA

PROVIDER: S-EPMC6623621 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Crystal structure of the amyloid-β p3 fragment provides a model for oligomer formation in Alzheimer's disease.

Streltsov Victor A VA Varghese Joseph N JN Masters Colin L CL Nuttall Stewart D SD

The Journal of neuroscience : the official journal of the Society for Neuroscience 20110101 4

Alzheimer's disease is a progressive neurodegenerative disorder associated with the presence of amyloid-β (Aβ) peptide fibrillar plaques in the brain. However, current evidence suggests that soluble nonfibrillar Aβ oligomers may be the major drivers of Aβ-mediated synaptic dysfunction. Structural information on these Aβ species has been very limited because of their noncrystalline and unstable nature. Here, we describe a crystal structure of amylogenic residues 18-41 of the Aβ peptide (equivalen ...[more]

PMID: 21273426

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Project description:Alzheimer's disease (AD) is an age-related neurodegenerative disease that affects 50 million people worldwide, with 10 million new cases occurring each year. The emotional and economic impacts of AD on patients and families are devastating. Approved treatments confer modest improvement in symptoms, and recently one treatment obtained accelerated approval from the United States Food and Drug Administration (FDA) and may have modest disease modifying benefit. Research over the past three decades has established a clear causal linkage between AD and elevated brain levels of amyloid β (Aβ) peptide, and substantial evidence now implicates soluble, non-fibrillar Aβ oligomers (AβOs) as the molecular assemblies directly responsible for AD-associated memory and cognitive failure and accompanying progressive neurodegeneration. The widely recognized linkage of elevated Aβ and AD spawned a comprehensive 20-year therapeutic campaign that focused primarily on two strategies - inhibition of the secretase enzymes responsible for Aβ production and clearance of Aβ peptide or amyloid plaques with Aβ-directed immunotherapeutics. Unfortunately, all clinical trials of secretase inhibitors were unsuccessful. Of the completed phase 3 immunotherapy programs, bapineuzumab (targeting amyloid plaque) and solanezumab (targeting Aβ monomers) were negative, and the crenezumab program (targeting Aβ monomers and to a small extent oligomers) was stopped for futility. Aducanumab (targeting amyloid plaques), which recently received FDA accelerated approval, had one positive and one negative phase 3 trial. More than 25 negative randomized clinical trials (RCTs) have evaluated Aβ-targeting therapeutics, yet none has directly evaluated whether selective blockage of disease-relevant AβOs can stop or reverse AD-associated cognitive decline. Here, we briefly summarize studies that establish the AD therapeutic rationale to target AβOs selectively, and we describe ACU193, the first AβO-selective immunotherapeutic to enter human clinical trials and the first positioned to test the AβO hypothesis of AD.

Dataset Information

Crystal structure of the amyloid-? p3 fragment provides a model for oligomer formation in Alzheimer's disease.

Publications

Crystal structure of the amyloid-β p3 fragment provides a model for oligomer formation in Alzheimer's disease.

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