Femtomolar-Acting Neuroprotective Peptides: Application For Inhibition Of Alzheimer'S Disease

Alzheimer's disease (AD) is characterized by death of selected brain cells that normally supply messenger molecules, forming short-term memory. The focus of the current work is the discovery and characterization of very short, readily available proteins (termed peptides) that provide protection to nerve cells at very low concentrations (among the lowest described to date).A major brain natural-protective short protein is vasoactive intestinal peptide (VIP) that affords neuronal defense through activation of proteins derived from glial cells (the brain support cells), such as activity-dependent neurotrophic factor (ADNF) and activity-dependent neuroprotective protein (ADNP). Drug design identified small and modified peptide fragments derived from VIP, ADNF, and ADNP, which can protect against damage in cell and animal models. The specific aim of the study is to optimize and choose the lead compounds. Tests include: simplified tissue-culture systems, brain-penetration assessments, and effects on short-term memory, in models relevant to AD. Selected lead compounds are further tested for mechanisms of protection, as well as potential side effects, and put forth for future clinical evaluations.Key findings include: (1) Lead compounds have been chosen: (a) the ADNP-derived peptide, NAP, (b) the fat-modified VIP, SNV, (c) the shortened VIP-derivative, stearyl-KKYL-NH2, and (d) the ADNF-related peptide, ADNF-9; (2) formulations for nasal spray administration have been optimized; (3) studies on mechanisms of protection identified selective gene activation and defense against inflammation. Advanced geneticengineering techniques are now utilized for the identification of novel interacting molecules, with NAP, the first lead planned for clinical trials, as the target.