Short Peptoid Evolved from the Key Hydrophobic Stretch of Amyloid-β42 Peptide Serves as a Potent Therapeutic Lead of Alzheimer's Disease.

Amyloid-β 42(Aβ42), an enzymatically cleaved (1-42 amino acid long) toxic peptide remnant, has long been reported to play the key role in Alzheimer's disease (AD). Aβ42 also plays the key role in the onset of other AD-related factors including hyperphosphorylation of tau protein that forms intracellular neurofibrillary tangles, imbalances in the function of the neurotransmitter acetylcholine, and even generation of reactive oxygen species (ROS), disrupting the cytoskeleton and homeostasis of the cell. To address these issues, researchers have tried to construct several strategies to target multiple aspects of the disease but failed to produce any clinically successful therapeutic molecules. In this article, we report a new peptoid called RA-1 that was designed and constructed from the hydrophobic stretch of the Aβ42 peptide, KLVFFA. This hydrophobic stretch is primarily responsible for the Aβ42 peptide aggregation. Experimental study showed that the RA-1 peptoid is stable under proteolytic conditions, can stabilize the microtubule, and can inhibit the formation of toxic Aβ42 aggregates by attenuating hydrophobic interactions between Aβ42 monomers. Furthermore, results from various intracellular assays showed that RA-1 inhibits Aβ42 fibril formation caused by the imbalance in AchE activity, reduces the production of cytotoxic reactive oxygen species (ROS), and promotes neurite outgrowth even in the toxic environment. Remarkably, we have also demonstrated that our peptoid has significant ability to improve the cognitive ability and memory impairment in rats exposed to AlCl and d-galactose (d-gal) dementia model. These findings are also validated with histological studies. Overall, our newly developed peptoid emerges as a multimodal potent therapeutic lead molecule against AD.