Thursday, April 25, 2024
4/25/2024
Alzheimer's disease (AD) is the most common form and devastating dementia. There are no effective approaches to specifically target and prevent AD pathogenesis. It is accepted that aggregated fibrillar forms of Aß peptides are prominent hallmarks and the major cause of AD due to their toxicity to neurons. As such, Aß aggregates are the potential targets for the intervention of AD, as targeting and removal of Aß fibrils or plaques is expected to eliminate the toxicity of Aß aggregates. Although the KLVFF peptide has been served as the major lead to develop potential probes to target Aß aggregation, it only weakly recognizes and inhibits Aß aggregation. Meanwhile, it is also susceptible to protease degradation. We recently developed a novel one-bead one-compound (OBOC) combinatorial library, from which we identified a potent peptidomimetic that is 100-fold more effective than KLVFF in disrupting Aß aggregation in vitro. This peptide material also removes the cytotoxicity of Aß aggregates towards N2a neuro-blastoma cells. Furthermore, this lead compound and its derivative can even significantly remove Aß plague deposited in the brain of the AD transgenic mice ex vivo. As such, our long-term goal is to develop novel biomaterials that can prevent, halt and cure AD. The objective of this proposal, is to advance our preliminary work by developing new OBOC libraries with enhanced chemodiversity and novel structural classes, so as to identify and develop more potent and effective AApeptide biomaterials that can target and inhibit fibrillar formation of Aß both in vitro and in vivo. We will first design and synthesize new OBOC gamma- AApeptide libraries with diverse functional groups and constraints by using a range of novel chemical approaches. Then we will use established screening assay to identify and optimize ligands that target and inhibit the aggregation of Aß peptides. The compounds with activity equivalent or better than the lead compound identified from the preliminary study will be used to study their ability to inhibit Aß aggregation both in vitro and in vivo on AD-transgenic mice. The proposed study is significant because there is no effective approaches for AD diagnosis and prevention. Our research will provide novel biomaterials to unravel AD pathogenies and to develop potential therapeutic agents for cure of AD. The proposed research is innovative because we not only provide a general approach for the development of novel class of biomaterials specially targeting Aß aggregates, in addition, this combinatorial approach can be easily extended to identify new materials targeting other amyloid diseases such as Huntington's disease and diabetes diseases.
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