Technical 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 FRï¡ï¬ï 4) 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 molecular targets and cognitive function behavioral tests with AD progression. In Phase II, we will conduct dose-finding and longer-term early and late intervention studies using multiple rodent AD models, immunotoxicity, etc. The t.s.-brain delivery could ultimately lead to the development of t.s. patches for AD.
Public Health Relevance Statement: Narrative (Public Health Relevance Statement) In the proposed project, we will use a novel nano formulation of curcuminoids to mitigate neuroinflammation and attenuate neurological diseases with emphasis on Alzheimer's disease (AD). In our approach, curcuminoids, known for their potent anti-inflammatory activity and activities inhibiting early brain markers of AD including neurofibrillary tangles and amyloid plaque formation, will be sequestered in exosomes (natural nanoparticles), isolated from standardized bovine colostrum powder, to increase bioavailability. The exosomes will be decorated with folic acid whose receptors are expressed in high levels in the brain, to target the brain sub tissues such as cortex and hippocampus, and the formulation is delivered by a novel trans-spinal (t.s.) topical route for efficient brain delivery and the efficacy assessed using transgenic mouse model of AD. Terms: <3xTg; 3xTg-AD mice; 3xTg-AD mouse; AD dementia; AD model; AD transgenic mice; Affect; Age; Alzheimer Type Dementia; Alzheimer disease dementia; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's Disease; Alzheimer's biomarker; Alzheimer's disease biological marker; Alzheimer's disease model; Alzheimer's disease therapeutic; Alzheimer's disease transgenic mice; Alzheimer's therapeutic; Alzheimer's transgenic mice; Alzheimers Dementia; Alzheimer's biological marker; Alzheimer's disease biomarker; Ammon Horn; Amyloid (Aß) plaques; Amyloid A4 Protein Precursor; Amyloid Plaques; Amyloid Protein Precursor; Amyloid beta-Protein Precursor; Amyloid ß-Protein Precursor; Animal Model; Animal Models and Related Studies; Anti-Inflammatories; Anti-Inflammatory Agents; Anti-inflammatory; Area; Attenuated; BACE; BACE1; BBB crossing; BDNF; Band Shift Mobility Assay; Bandshift Mobility Assay; Bioavailability; Biodistribution; Biological Availability; Biological Markers; Body Tissues; Bovine Species; Brain; Brain Nervous System; Brain region; Brain-Derived Neurotrophic Factor; Cattle; Clinical; Clinical Research; Clinical Study; Cognitive; Colostrum; Cornu Ammonis; Curcumin; Data; Degenerative Neurologic Disorders; Development; Diferuloylmethane; Disease; Disease Progression; Disorder; Dose; Drug Delivery; Drug Delivery Systems; Drugs; Dryness; Effectiveness; Electrophoretic Mobility Shift Assay; Encephalon; FDA approved; Folate; Folic Acid; Formulation; Gene Expression; Goals; Hepatic; Hippocampus; Hortega cell; Human; Immunoassay; In Vitro; Inflammation; Inflammation Mediators; Inflammatory Response; Intermediary Metabolism; Intervention Studies; Investigators; Label; Lead; Mediating; Medication; Metabolic Processes; Metabolism; Mice; Mice Mammals; Microglia; Minor; Mobility Shift Assay; Modern Man; Molecular Target; Murine; Mus; Nervous System Degenerative Diseases; Nervous System Diseases; Nervous System Disorder; Neural Degenerative Diseases; Neural degenerative Disorders; Neuritic Plaques; Neuroblastoma; Neurodegenerative Diseases; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurologic Degenerative Conditions; Neurologic Disorders; Neurological Disorders; Oral; Pb element; Persons; Pharmaceutical Preparations; Phase; Physiologic Availability; Plants; Powder dose form; Powders; Primary Senile Degenerative Dementia; Progress Reports; Property; Pteroylglutamic Acid; Receptor Protein; Reporting; Research; Research Personnel; Researchers; Rodent; Rodentia; Rodents Mammals; Route; SIRT1; SIRT1 gene; Senile Plaques; Sirtuin 1; Spinal; Standardization; System; Testing; Therapeutic; Tissues; Toxic effect; Toxicities; Transgenic Mice; Turmeric Yellow; Vitamin M; abeta accumulation; abeta aggregation; ages; alleviate symptom; alzheimer model; ameliorating symptom; amyloid beta accumulation; amyloid beta aggregation; amyloid beta plaque; amyloid precursor protein; amyloid ß accumulation; amyloid ß aggregation; amyloid-b plaque; attenuate; attenuates; aß accumulation; aß aggregation; aß plaques; behavior test; behavioral test; beta-secretase 1; beta-site APP cleaving enzyme 1; beta-site amyloid precursor protein cleaving enzyme 1; bio-markers; biologic marker; biomarker; blood-brain barrier crossing; bloodbrain barrier crossing; bovid; bovine; brain tissue; cognitive function; cored plaque; cow; curcumin II; cyanine; decrease symptom; degenerative diseases of motor and sensory neurons; degenerative neurological diseases; demethoxy-curcumin; demethoxycurcumin; determine efficacy; developmental; diffuse plaque; donepezil; drug standard; drug/agent; efficacy analysis; efficacy assessment; efficacy determination; efficacy evaluation; efficacy examination; evaluate efficacy; examine efficacy; exosome; experience; fewer symptoms; folate carrier; folate receptor; folate-binding protein; folate-methotrexate transporter; folic acid binding protein; folic acid receptor; gel shift assay; gitter cell; heavy metal Pb; heavy metal lead; hippocampal; immunotoxicity; inflammatory mediator; intervention research; interventional research; interventional study; interventions research; memapsin 2; mesoglia; methotrexate-binding protein; microglial cell; microgliocyte; model of animal; monodemethoxycurcumin; nano formulation; nano particle; nano-sized particle; nanoformulation; nanoparticle; nanosized particle; neural inflammation; neuroblastoma cell; neurodegenerative illness; neurofibrillary degeneration; neurofibrillary lesion; neurofibrillary pathology; neuroinflammation; neuroinflammatory; neurological disease; neuroprotection; neuroprotective; novel; p-tau; p-Ï; perivascular glial cell; phospho-tau; phospho-Ï; phosphorylated tau; post-translational modification of tau; posttranslational modification of tau; pre-clinical study; preclinical study; primary degenerative dementia; protein expression; public health relevance; receptor; reduce symptoms; relieves symptoms; response to therapy; response to treatment; senile dementia of the Alzheimer type; site targeted delivery; small molecule; symptom alleviation; symptom reduction; symptom relief; tangle; targeted delivery; tau phosphorylation; tau posttranslational modification; tau-1; therapeutic response; therapy response; toxic reaction in immunology; treatment response; treatment responsiveness; vitamin Bc; ß-secretase 1; ß-site APP cleaving enzyme 1; Ï phosphorylation
