Technical Abstract Neurodegenerative disorders affect over 40 million people worldwide and most, if not all, are mediated by inflammation. Even though several drugs are approved by the FDA for treating neurological disorders such as Alzheimer’s disease (AD), their efficacy as AD therapeutics has not been realized as extremely low levels of the drug reach the brain. The goal of this Phase I project is to develop an effective targeted delivery system for the bioactive curcuminoids, curcumin (CUR) and bisdemethoxycurcumin (BDMC), to mitigate AD and potentially other neuroinflammatory diseases. We will apply our extensive experience in exosomes, drug delivery, plant therapeutics and inflammatory responses for efficient, targeted delivery of bioactive curcuminoids to the microenvironment of the brain where progressive increase in inflammation, amyloid plaque formation and neurofibrillary tangles ultimately leads to manifestation of AD. We hypothesize that the combined administration of CUR and BDMC will be highly effective at ameliorating neuroinflammation and aberrant AD-related gene expression returning these biomarkers to pre-disease levels due to synergistic action via different mechanisms. We also hypothesize that folic acid (FA)-functionalized exosomal formulations administered using a novel topical, trans-spinal (t.s.) route will provide enhanced targeting to AD-related regions of the brain, including the cortex and hippocampus. Exosomes cross the BBB efficiently and areas of the brain associated with AD have high levels of folate receptors (FRs). Thus, t.s.-administered FA-ExoCUR/BDMC will deliver higher payload to the brain vs. conventional routes. Our hypotheses are supported by 1) effective drug loading of curcuminoids onto bovine colostrum exosomes, 2) higher levels (~5-fold brain) of curcuminoids in rodent tissues after oral treatment with Exo-curcuminoids than free curcuminoids, 3) FA-exosomes can increase drug delivery to the brain which contains high expression of FR4) reduced NFκB accumulation and decreased abundance of phosphorylated Tau (pTau) and amyloid precursor protein (APP) expression in brain lysates of mice treated orally with ExoCUR/BDMC in concurrence with increased expression of brain-derived neurotrophic factors (BDNF) comparable to levels in age- matched untreated WT mice while free CUR/BDMC was ineffective, and 5) higher brain accumulation of exosomes in mice treated via t.s. route vs. the traditional i.v. route. Investigators experienced in exosomes, drug delivery, plant bioactives and animal models, leveraging extensive experience of Dr. Robert Friedland in AD research, will pursue the following specific aims: Aim 1. Optimize ExoCUR/BDMC formulations and determine biodistribution and toxicity in WT mice. Aim 2. Determine efficacy of FA-functionalized ExoCUR/BDMC formulations in AD mice. This project will provide proof-of-principle for the effectiveness of t.s.-delivered FA-ExoCUR/BDMC on the modulation of key mole...