Nanobody specific for oligomeric beta-amyloid stabilizes nontoxic form

While accumulation and deposition of beta amyloid (A beta) is a primary pathological feature of Alzheimer's disease (AD), increasing evidence has implicated small, soluble oligomeric aggregates of A beta as the neurotoxic species in AD. Reagents that specifically recognize oligomeric morphologies of A beta have potential diagnostic and therapeutic value. Using a novel biopanning technique that combines phage display technology and atomic force microscopy, we isolated the nanobody E1 against oligomeric A beta. Here we show that E1 specifically recognizes a small oligomeric A beta aggregate species distinct from the species recognized by the A4 nanobody previously reported by our group. While E1, like A4, blocks assembly of A beta into larger oligomeric and fibrillar forms and prevents any A beta induced toxicity toward neuronal cells, it does so by binding a small A beta oligomeric species, directing its assembly toward a stable nontoxic conformation. The E1 nanobody selectively recognizes naturally occurring A beta aggregates produced in human AD brain tissue indicating that a variety of morphologically distinct A beta aggregate forms occur naturally and that a stable low-n nontoxic A beta form exists that does not readily aggregate into larger forms. Because E1 catalyses the formation of a stable nontoxic low-n A beta species it has potential value as a therapeutic reagent for AD which can be used in combination with other therapeutic approaches. (C) 2012 Elsevier Inc. All rights reserved.