Induction of hippocampal long term potentiation (LTP) deficit by soluble amyloid-beta (Abeta) peptide oligomers (dimers, trimers, etc.) is believed to be one pathological mechanism associated with Alzheimer’s disease (AD). Prior investigation by the Selkoe group into Abeta-LTP inhibition revealed that “co-administering antibodies to the Abeta N-terminus prevented LTP and [long term depression (LTD)] deficits (of hippocampus cells), whereas antibodies to the CHC or C-terminus were less effective” (Shankar et al., Nature Medicine, 2008). Due to the side effects of administering effective concentrations of antibodies to the brain, such as brain swelling and microhemorrhaging, we searched for peptide ligands that will bind to the N-terminus of Abeta using rational design and combinatorial synthesis. For rationally designed peptides, we used residue-pairing information from A2T, a naturally occurring protective mutant against AD, which forms intramolecular electrostatic interactions between the N-terminus and the charged residues surrounding the central hydrophobic core. For combinatorial synthesis, we screened over 78,000 heptamer peptides composed of amino acids, which naturally pair with the target sequence. Additional information to guide the design of ligands that bind specifically to the N-terminus of Abeta was obtained from natural split-intein pairs. Here, we identify the top binding “hits”, as quantified by binding affinity using electrospray ionization mass spectrometry, and discuss their binding specificity and stoichiometry.

Peptide ligands bind to electrostatic domains of Abeta

251st National Meeting (2016)

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