Soluble amyloid-beta oligomer (A beta O) is believed to be a reliable molecular biomarker for the diagnosis of Alzheimer's disease (AD) because of its high toxicity for neuronal synapse and higher concentration level in cerebrospinal fluid sample from AD patient than from control individual. At present, it is critical to develop a simple method for A beta O detection with low cost as well as high sensitivity and selectivity. In this work, we reported an antibody-free electrochemical method for the detection of ADO based on the specific interaction between A beta O and PrP(95-110) peptide, a segment of cellular prion protein. Specifically, cysteine-containing PrP(95-110) peptide was first immobilized on a gold electrode for the capture of A beta O. Then, alkaline phosphatase-conjugated PrP(95-110) was used for the recognition of the captured A beta O and the generation of electroactive species. Furthermore, an "outer-sphere to inner-sphere" electrochemical-chemical-chemical (ECC) redox cycling using ferrocene methanol as the redox mediator was employed to enhance the detection sensitivity. As a result, a detection limit of 3 pM for equivalent monomer was achieved. The amenability of this method to A beta O analysis in a biological matrix was demonstrated by assays of A beta O in serum samples. (C) 2015 Elsevier B.V. All rights reserved.