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