Novel Combinations of Natural Product Compounds for Treatment of Alzheimer Disease and Related Dementias

PROJECT SUMMARY/ABSTRACT In response to National Institute on Aging's (NIA) strategic plan and PAS-19-317, we propose novel therapeuticsto treat Alzheimer disease and related dementias (ADRDs). We have developed novel combinations of three natural product compounds, which modulate complementary pathways in multiple types of CNS cells (i.e., neurons, microglia) associated with AD pathology. These compounds were originally discovered through our previous computational systems biology research on AD target discovery and drug repurposing funded by NIA AMP-AD consortium where we identified over 6000 potential targets and prioritized more than 3000 candidate compounds, including natural compounds, FDA-approved drugs, and small-molecules. These compounds were identified via analysis of multi-omics data from large-scale post-mortem brain tissues of AD patients using our computational systems biology approach. In this project, we propose to further confirm the safety in wild-type (i.e., C57BL6/J mice) and therapeutic efficacy using an established murine model of AD (i.e., 3xTg mice) for our novel combinations of natural product compounds. Additionally, we will validate the correlation of our novel sex- and APOE genotype- specific serum-based metabolic biomarkers and additional protein biomarkers with the therapeutic effects of our treatment in this AD mice model. We hypothesize that these natural product combinations will prove to be safe and effective therapeutics for treatment of ADRD. To address this hypothesis, we proposed the following three aims: Aim 1: To evaluate systemic and central toxicity of NAD+/PEITC and NADH/PEITC. In this aim, we will first validate the compound structure and formulation stability with LC-MS and NMR. Next, we will use male and female C57BL6/J aged 6 months and 15 months to test brain, liver, kidney, and heart toxicity of our combinations during the acute (3 days), subacute (7 days), and chronic (28 days) periods post-dose. Aim 2: To evaluate therapeutic effects of these drug combinations on AD Biomarkers and Functional Cognitive Performance in 3xTg mice. Here, we will measure effects of our therapeutic combinations on brain levels of amyloid beta proteins (i.e., Ab(1-38), Ab(1-40), Ab(1-42)) and hyperphosphorylated tau. We will also test effects of our combinations of natural products on neurocognitive performance using the novel object recognition test and the Morris water maze. All studies in Aim 2 will be conducted in male and female 3xTg mice aged 6 months and 15 months. Aim 3: To evaluate additional blood-based therapeutic biomarkers of these drug combinations. Using blood samples collected from 15-month-old male and female 3xTg mice (Aim 2), we will validate novel blood-based metabolic and proteomics biomarkers for evaluation of therapeutic responses of our combinations via metabolomics and proteomics data analysis. Our preliminary results on both in-vitro and in-vivo model have demonstrated great promise on significant neuroprotection, stimulation of microglial phagocytosis and improving working memory of 3xTG mice. Upon the success of this project, we will be ready to further confirm the safety and therapeutic effectsof these combinations of compounds for MCI and/or very early-stage of AD in a clinical study.