Aqueously soluble oligomers of amyloid β-peptide (oAβ) may be the principal neurotoxic forms of Aβ in Alzheimer disease (AD), initiating downstream events that include tau hyperphosphorylation, neuritic/synaptic injury, microgliosis and neuron loss. Synthetic oAβ has been extensively studied, but little is known about the biochemistry of natural oAβ in human brain, even though it is more potent than simple synthetic peptides and comprises truncated and modified Aβ monomers. We hypothesized that monoclonal antibodies specific to neurotoxic oAβ could be used to isolate it for further study. Here we report a unique human monoclonal antibody (B24) raised against synthetic oAβ that potently prevents AD brain oAβ-induced impairment of hippocampal long-term potentiation. B24 binds natural and synthetic oAβ and a subset of amyloid plaques, but only in the presence of Ca2+. The Aβ N-terminus is required for B24 binding. Hydroxyapatite chromatography revealed that natural oAβ is highly avid for Ca2+. We took advantage of the reversible Ca2+-dependence of B24 binding to perform non-denaturing immunoaffinity isolation of oAβ from AD brain soluble extracts. Unexpectedly, the immunopurified material contained amyloid fibrils visualized by electron microscopy and amenable to further structural characterization. B24-purified human oAβ inhibited mouse hippocampal LTP. These findings identify a calcium-dependent method for purifying bioactive brain oAβ, at least some of which appears fibrillar.
