Abstract
The deposition of Aβ peptide in the brain is the key event in Alzheimer disease progression. Therefore, the prevention of Aβ self assembly into disease-associated oligomers is a logical strategy for treatment. π stacking is known to provide structural stability to many amyloids; two phenylalanine residues within the Aβ 14–23 self recognition element are in such an arrangement in many solved structures. Therefore, we targeted this structural stacking by substituting these two phenylalanine residues with their D-enantiomers. The resulting peptides were able to modulate Aβ aggregation in vitro and reduce Aβ cytotoxicity in primary neuronal cultures. Using kinetic analysis of fibril formation, electron microscopy and dynamic light scattering characterization of oligomer size distributions, we demonstrate that, in addition to altering fibril structural characteristics, these peptides can induce the formation of larger amorphous aggregates which are protective against toxic oligomers, possibly because they are able to sequester the toxic oligomers during co-incubation. Alternatively, they may alter the surface structure of the oligomers such that they can no longer interact with cells to induce toxic pathways.
Highlights
Alzheimer’s disease (AD) is expected to affect 14 million North Americans by the middle of this century, yet studies have failed to find effective disease-modifying treatments
Our results indicate that the generated peptides do not form Thioflavin T (ThT) positive aggregates, but can be incorporated into Aβ 1–42 fibrils and influence the toxicity of Aβ 1–42 oligomers, possibly by sequestering the more toxic oligomers into large amorphous aggregates
Given the proposed π -stacking that occurs in the core region of the Aβ structure (Fig 1A–1C), we theorized that altering the orientation of the planar aromatic residues would interfere with fibril formation and / or the formation of a toxic species
Summary
Alzheimer’s disease (AD) is expected to affect 14 million North Americans by the middle of this century, yet studies have failed to find effective disease-modifying treatments. Because the accumulation of beta amyloid (Aβ) is thought to trigger AD pathogenesis[1,2,3,4,5,6], Aβ has been a logical target for therapeutic interventions[7,8]. To directly interfere with the Aβ cascade, the ideal therapeutic compound would have specificity for pathological Aβ aggregates, reduce aggregation and / or toxicity of the aggregates, be non-toxic itself, and be able to cross the bloodbrain barrier. One way to prevent the accumulation of pathological Aβ, is to target the self recognition elements (SREs) that promote Aβ aggregation into toxic oligomers or fibrils. Oligomers are more toxic than fibrils, but both are associated with disease[9].
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