PROJECT SUMMARY Alzheimer's disease is associated with multiple factors, including but not limited to amyloid plaque formation, tau protein entanglement, enzyme degradation and inflammation. Inflammation is implicated in many aging diseases and in the central nervous system (CNS) is associated with the CCR5 gene that increases with age. CCR5 has been correlated with impairments in memory consolidation in aged mice, which was reversed with a CCR5 knockout and an FDA approved drug that inhibits this receptor. We propose to develop targeted nanoparticles of an anti-CCR5 drug, and evaluate its impact on brain inflammation and AD. In Phase I, we will: (i) Nanoencapsulate anti-CCR5 drug in targeted and non-targeted, long circulating, pegylated nanoparticles utilizing a proprietary solvent-free technology, and characterize the size and distribution of the nanoparticles, encapsulation or loading efficiency, and in vitro release characteristics; and (ii) Evaluate the impact of the anti-CCR5 drug nanoparticles on in vitro models of brain inflammation and BBB penetration to select best candidates for in vivo studies, perform pharmacokinetic, biodistribution and toxicity studies in wild-type mice and efficacy studies in a transgenic mouse model of Alzheimer's disease. In Phase II, we will more rigorously characterize the nanoparticles, conduct extensive in vitro and in vivo studies, and scale- up manufacturing towards conducting IND-enabling studies and filing an IND for Phase I and/or Phase IIb studies. We will then out-license the developed technologies and products to a multinational pharmaceutical or biotechnology company.