Recognition of Abeta monomeric helix

Alzheimer’s disease (AD) is the most devastating dementia causing severe global concern. Although the mechanism of AD pathogenesis is still under debate, it is widely accepted that aggregated fibrillar forms of Aβ peptides are prominent hallmarks and the major cause of AD due to their toxicity to neurons. Therefore, Aβ aggregates are the potential targets for the intervention of AD, as targeting and removal of Aβ fibrils or plaques is expected to eliminate the neuronal toxicity of Aβ aggregates. However, eradication of total Aβ peptides by antibodies such as the new drug aducanumab could lead to severe side effects, whereas anti-Aβ aggregation by β-sheet mimetics could only prevent or delay the process of aggregation process and could not disrupt the formed/existing Aβ aggregation. Therefore, development of more effective molecular probes that not only prevent but also disrupt Aβ fibril formation is still in an urgent need. In contrast to the use of β-sheet mimetics to block Aβ fibrillar growth, recently we designed a series of helical peptidomimetics that can tightly bind and stabilize monomeric helical Aβ and thereby shifting the equilibrium of Aβ conformation into off-pathway structure, leading to both potent prevention and disruption of Aβ aggregation, as well as significant enhancement of neuro cell growth and dendrite branching without virtually any cytotoxicity. Furthermore, this lead compound could remove Aβ plague deposited in the brain of the AD transgenic mouse and completely recover the memory of mice in the behavior test. As such, our long-term goal is to develop novel biomaterials that can prevent, halt and cure AD. The objective of this proposal, which is the first step to achieve the long-term goal, is to advance our preliminary work by rationally designing structurally related analogues of the current lead, so as to identify and develop more potent and effective compounds that can tightly bind and stabilize Aβ monomer and thus prevent and disrupt Aβ aggregation both in vitro and in vivo. We will first design helical peptidic foldamer bearing diverse functional groups and closely mimic the binding pattern of our lead compound. Then we will use our established in vitro assays such as 2D-NMR and kinetic binding assays to identify and optimize our designed compounds that target and inhibit the aggregation of Aβ peptides. The compounds with activity equivalent or better than the lead compound will be used to study their ability to inhibit Aβ aggregation both in vitro and in vivo in AD-transgenic mice. The proposed study is significant because there is no effective therapeutic strategy for AD diagnosis and prevention. Our research will provide molecules with novel mechanism to unravel AD pathogenies and to develop potential molecular probes and therapeutic agents for cure of AD. The proposed research is innovative because we not only provide a new strategy for the development of novel class of foldameric prevent and disrupt Aβ aggregation, in addition, this approach of rational design for the recognition of Aβ surface can be easily extended to identify new materials targeting other amyloid diseases such as Huntington’s disease and diabetes diseases.