Chemical Probes That Selectively Recognize the Earliest Aβ Oligomers in Complex Mixtures

Abstract

Alzheimer’s disease (AD) is characterized by the self-assembly of amyloid beta (Aβ) peptides. Recent models implicate some of the earliest Aβ oligomers, such as trimers and tetramers, in disease. However, the roles of these structures remain uncertain, in part, because selective probes of their formation are not available. Towards that goal, we generated bivalent versions of the known Aβ ligand, the pentapeptide KLVFF. We found that compounds containing sufficiently long linkers (~19 to 24 Å) recognized primarily Aβ trimers and tetramers, with little binding to either monomer or higher order structures. These compounds might be useful probes for early Aβ oligomers.

Electrochemical detection of amyloid-β oligomer with the signal amplification of alkaline phosphatase plus electrochemical–chemical–chemical redox cycling

“…Furthermore, recent insights have indicated that small oligomeric assemblies of Aβ, in contrast to monomeric and fibrillar species, are toxic for neuronal synapses and exist in cerebrospinal fluid sample from AD patient at higher concentration level than from control individual [6][7][8]. Thus, Aβ oligomer (AβO) comprising of 50-100 Aβ monomers has been regarded as a reliable molecular biomarker for AD diagnosis and the crucial target for therapeutic intervention [5,[9][10][11].…”

A Foldamer-Dendrimer Conjugate Neutralizes Synaptotoxic β-Amyloid Oligomers

“…The multivalent structures containing the KLVFF segment [61]–[63] target the LMW oligomers through assumed incorporation into the β-sheet structure. The selective interaction with LMW oligomers have been demonstrated for dimeric structures [62]. The aggregation process could also be inhibited this way, but protecting effects against the toxic Aβ oligomers have not been described.…”

Engineering of a peptide probe for β-amyloid aggregates

“…The tested antibodies include 6E10, 4G8, anti-Ab (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) and 9F1, recognizing Ab M1-K16, Ab L17-E22, Ab E22-M35 and Ab I32-V39, respectively. The tested antibodies include 6E10, 4G8, anti-Ab (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) and 9F1, recognizing Ab M1-K16, Ab L17-E22, Ab E22-M35 and Ab I32-V39, respectively.…”

“…The physiological Ab concentration is in the range of low nM in brain 22,52,65 and low pM in body fluids, 66,67 requiring higher sensitivity for reliable in vivo or ex vivo detection using KLVFWAK. While multivalent peptide ligands for Ab were previously developed based on KLVFF, 31,33,70 their functional affinity and specificity were difficult to optimize systematically. For example, one may consider increasing Ab aggregate-affinity by exploiting multivalency of KLVFWAK.…”

“…[23][24][25] Antibodies and antibody fragments must be well-folded in order for target binding but often suffer from insufficient conformational stability, 26 which limits their applications and further optimizations. [29][30][31][32][33][34] Unfortunately, most Ab-derived peptides display relatively low affinity for Ab aggregates compared to Ab monomers [29][30][31][32] and exhibit high self-aggregation propensity, [29][30][31]35,36 making Ab-derived segments ill-suited to profile Ab aggregates. Rational and combinatorial sequence variations as well as multi-valent displays are readily available to further engineer peptide ligands for improved affinity and specificity.…”