title: New ELISAs with high specificity for soluble oligomers of amyloid β-protein detect natural Aβ oligomers in human brain but not CSF.
abstract: BACKGROUND
  Soluble oligomers of amyloid ß-protein (Aß) have been increasingly linked to synaptic dysfunction, tau alteration, and neuritic dystrophy in Alzheimer's disease (AD) and mouse models. There is a great need for assays that quantify Aß oligomers with high specificity and sensitivity.
  
  
  METHODS
  We designed and validated two oligomer-specific (o-) enzyme-linked immunoassays (ELISAs) using either an Aß aggregate-selective monoclonal for capture and a monoclonal to the free N-terminus for detection, or the latter antibody for both capture and detection.
  
  
  RESULTS
  The o-ELISAs specifically quantified pure oligomers of synthetic Aß with sizes from dimers up to much larger assemblies and over a wide dynamic range of concentrations, whereas Aß monomers were undetectable. Natural Aß oligomers of similarly wide size and concentration ranges were measured in extracts of AD and control brains, revealing >1000-fold higher concentrations of Aß oligomers than monomers in the soluble fraction of AD cortex. The assays quantified the age-related rise in oligomers in hAPP transgenic mice. Unexpectedly, none of 90 human cerebrospinal fluid (CSF) samples gave a specific signal in either o-ELISA.
  
  
  CONCLUSIONS
  These new o-ELISAs with rigorously confirmed specificity can quantify oligomer burden in human and mouse brains for diagnostic and mechanistic studies and for AD biomarker development. However, our data raise the likelihood that the hydrophobicity of Aß oligomers makes them very low in number or absent in aqueous CSF.
authors: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors: Ting
authors: T
authors: Yang
authors: Soyon
authors: S
authors: Hong
authors: Tiernan
authors: T
authors: O'Malley
authors: Reisa A
authors: RA
authors: Sperling
authors: Dominic M
authors: DM
authors: Walsh
authors: Dennis J
authors: DJ
authors: Selkoe
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000175:diagnosis*; D016229:Amyloid beta-Peptides / Q000032:analysis*; D000818:Animals; D000911:Antibodies, Monoclonal; D015415:Biomarkers / Q000032:analysis / Q000134:cerebrospinal fluid; D015153:Blotting, Western; D001921:Brain / Q000473:pathology*; D002648:Child; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods*; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D007223:Infant; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D010446:Peptide Fragments / Q000032:analysis / Q000134:cerebrospinal fluid; D012680:Sensitivity and Specificity; D055815:Young Adult
chemical_list: D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D015415:Biomarkers; D010446:Peptide Fragments
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