Nanobody specific for oligomeric beta-amyloid stabilizes nontoxic form

Srinath Kasturirangan, Lin Li, Sharareh Emadi, Shanta Boddapati, Philip Schulz, Michael Sierks

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)1320-1328
Number of pages9
JournalNeurobiology of Aging
Volume33
Issue number7
DOIs
StatePublished - Jul 2012

Keywords

  • AFM
  • Alzheimer's disease
  • Beta amyloid
  • Nanobody
  • Oligomers

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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