TY - JOUR T1 - Crystal Structure of the Amyloid-β p3 Fragment Provides a Model for Oligomer Formation in Alzheimer's Disease JF - The Journal of Neuroscience JO - J. Neurosci. SP - 1419 LP - 1426 DO - 10.1523/JNEUROSCI.4259-10.2011 VL - 31 IS - 4 AU - Victor A. Streltsov AU - Joseph N. Varghese AU - Colin L. Masters AU - Stewart D. Nuttall Y1 - 2011/01/26 UR - http://www.jneurosci.org/content/31/4/1419.abstract N2 - 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 (equivalent to the p3 α/γ-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 Aβ 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 Aβ oligomers and reveals conserved elements consistent with residues and motifs predicted as critical in Aβ folding and oligomerization, thus potentially providing a model system for nonfibrillar oligomer formation in Alzheimer's disease. ER -