A human scFv antibody that targets and neutralizes high molecular weight pathogenic amyloid-? oligomers.

ABSTRACT: Brain accumulation of soluble oligomers of the amyloid-? peptide (A?Os) is increasingly considered a key early event in the pathogenesis of Alzheimer's disease (AD). A variety of A?O species have been identified, both in vitro and in vivo, ranging from dimers to 24mers and higher order oligomers. However, there is no consensus in the literature regarding which A?O species are most germane to AD pathogenesis. Antibodies capable of specifically recognizing defined subpopulations of A?Os would be a valuable asset in the identification, isolation, and characterization of AD-relevant A?O species. Here, we report the characterization of a human single chain antibody fragment (scFv) denoted NUsc1, one of a number of scFvs we have identified that stringently distinguish A?Os from both monomeric and fibrillar A?. NUsc1 readily detected A?Os previously bound to dendrites in cultured hippocampal neurons. In addition, NUsc1 blocked A?O binding and reduced A?O-induced neuronal oxidative stress and tau hyperphosphorylation in cultured neurons. NUsc1 further distinguished brain extracts from AD-transgenic mice from wild type (WT) mice, and detected endogenous A?Os in fixed AD brain tissue and AD brain extracts. Biochemical analyses indicated that NUsc1 targets a subpopulation of A?Os with apparent molecular mass greater than 50 kDa. Results indicate that NUsc1 targets a particular A?O species relevant to AD pathogenesis, and suggest that NUsc1 may constitute an effective tool for AD diagnostics and therapeutics.

SUBMITTER: Sebollela A 

PROVIDER: S-EPMC5752625 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature