Multifunctional Architectures of Cyclic Dipeptide Copolymers and Composites, and Modulation of Multifaceted Amyloid-ß Toxicity

Alzheimer's disease (AD) is a major neurodegenerative disorder primarily characterized by the ss-amyloid (A ss 42) misfolding and aggregation-associated multifaceted amyloid toxicity encompassing oxidative stress, neuronal death, and severe cognitive impairment. Modulation of A ss 42 aggregation via various structurally anisotropic macromolecular systems is considered effective in protecting neuronal cells. In this regard, we have developed a cyclic dipeptide (CDP)-based copolymer (CP) and explored its material and biomedical properties. Owing to the structural versatility, CDP-CP forms solvent-dependent anisotropic architectures ranging from dense fibers and mesosheets to vesicles, which are shown to interact with dyes and nanoparticles and mimic synthetic protocells, providing a conceptually new approach to achieve advanced functional materials with the hierarchical organization. CP upon interaction with gold nanoparticles (GNP) and polyoxometalate (POM) generated faceted architectures (CP-GNP) and the nanocomposite (CP-POM), respectively. CP-GNP and CP-POM have shown remarkable ability to inhibit A ss 42 aggregation, dissolve the preformed aggregates, and scavenge reactive oxygen species (ROS) to ameliorate multifaceted amyloid toxicity. In cellulo studies show that CP-GNP and CP-POM protect neuronal cells from A ss 42-induced toxicity and reduce lipopolysaccharide (LPS)-activated neuroinflammation at sub-micromolar concentration. To our knowledge, this is the first report on the hierarchical organization of CDP-CP into 1D-to-2D architectures and their organic-inorganic hybrid nanocomposites to combat the multifaceted amyloid toxicity.

Automated summary

Alzheimer's disease is a major neurodegenerative disorder characterized by the misfolding and aggregation of β-amyloid protein, leading to neuronal death and cognitive impairment. A cyclic dipeptide-based copolymer has been developed and shown to protect neuronal cells by inhibiting Aβ42 aggregation and reducing amyloid toxicity. The copolymer also interacts with gold nanoparticles and polyoxometalate, forming novel nanocomposites that further enhance its protective effects.