β-amyloid monomer scavenging by an anticalin protein prevents neuronal hyperactivity

Abstract

Abstract Hyperactivity mediated by synaptotoxic β-amyloid (Aβ) oligomers is one of the earliest forms of neuronal dysfunction in Alzheimer’s disease. In the search for a preventive treatment strategy, we tested the effect of scavenging Aβ peptides prior to Aβ plaque formation. We demonstrate that an Aβ binding anticalin protein (Aβ-anticalin) can suppress early neuronal hyperactivity. Unexpectedly, the sole targeting of Aβ monomers was sufficient for the hyperactivity-suppressing effect of the Aβ-anticalin. Biochemical and neurophysiological analysis suggest that Aβ-anticalin-dependent depletion of naturally secreted Aβ monomers interrupts aggregation to neurotoxic oligomers and, thereby, prevents synaptic dysfunction. Our results demonstrate that Aβ monomer scavenging can reverse early neuronal dysfunction and, thus, offers a promising strategy for the preventive treatment of AD.