Pro-Electrophilic Drugs PEDs for Alzheimer's Disease

用于治疗阿尔茨海默病的亲电药物 PED

• 批准号: 10230417
• 负责人: STUART A LIPTON
• 金额: $ 88.56万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10230417
• 关键词: AD transgenic mice; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Anti-Inflammatory Agents; Antioxidants; Astrocytes; Back; Behavioral; Binding; Brain; Cell Nucleus; Cells; Cellular Stress; Cerebrum; Clinical; Clinical Trials; Curcumin; Cytoplasm; Data; Elements; Enzymes; Exhibits; Formulation; Fumarates; Genes; Genetic Transcription; Glutathione; Goals; Heart; Herb; Hippocampus (Brain); Histologic; Histology; Human; Injections; J20 mouse; Lead; Learning; Lentivirus Vector; Memory; Modeling; Mus; Mutant Strains Mice; Nervous system structure; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Normal Cell; Nuclear; Organoids; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Pattern; Pharmaceutical Preparations; Phase; Prodrugs; Production; Property; Proteins; Publications; Reporting; Rodent; Rosemary; Route; Senile Plaques; Site; Sulfhydryl Compounds; Synapses; Tauopathies; Testing; Therapeutic; Toxic effect; Toxicity Tests; Transcriptional Activation; Transgenic Mice; Transgenic Organisms; Work; age related; cooking; drug candidate; drug discovery; effectiveness testing; frontal lobe; heme oxygenase-1; improved; in vitro Model; in vivo; induced pluripotent stem cell; innovation; lead optimization; mouse model; nervous system disorder; neurobehavior; neuroinflammation; neuroprotection; novel; novel therapeutics; nuclear factor-erythroid 2; oxidation; oxidative damage; prevent; promoter; response; retinal damage; salvin; side effect; stroke model; tau Proteins; transcription factor

We propose a novel target and new drug to treat Alzheimer’s disease (AD) via the Nrf2 transcriptional pathway. Our drug candidates for this target are currently at the stage of active hit-to-lead optimization, as described below. As background, AD is a condition with loss of synapses and neurons in the brain, characterized by the presence of amyloid beta (Aβ) plaques and tau tangles, which cause damage to synapses and neurons at least partially via oxidative stress. Our prior studies have indicated that carnosic acid (CA), a component compound in the herb Rosemary, can protect neurons and synapses from damage caused by oxidative stress by activating the Nrf2 transcriptional pathway. Our Preliminary Data show that CA treatment ameliorates various behavioral and histological deficits in AD transgenic mutant mice, while showing no significant side effects. Activation of the Keap1/Nrf2 (kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2) pathway upregulates transcription of phase II antioxidant and anti-inflammatory proteins. We and others have shown that this can be a valuable therapeutic strategy in several neurodegenerative diseases. Here, we further test this approach in mouse models of AD using carnosic acid (CA), which we have shown in our publications to activate the Keap1/Nrf2 pathway. CA is known to be clinically tolerated because of its presence in herbs like Rosemary. Conversely, in humans with AD, a decreased expression pattern of Nrf2 in hippocampal neurons and astrocytes, as well as a significant decrease in nuclear Nrf2 levels in frontal cortex, have been reported. The Keap1/Nrf2 pathway can be activated by an electrophilic compound when it reacts with a specific thiol on Keap1, releasing Nrf2 in the cytoplasm to enter the nucleus where it binds to the antioxidant responsive element (ARE) on the promoters of phase II genes. An important issue clinically with regard to electrophilic drugs (such as dimethyl fumarate, curcumin, and Bardoloxone) is that they not only react with Keap1 to activate Nrf2, but they also non-specifically react with other thiol groups, which may explain both their actions and side effects. Our alternative, innovative strategy to avoid such side effects is to use pro-electrophilic compounds that are activated by the very oxidation in redox-stressed cells that is injurious. The compound CA represents a starting point for such a pro-electrophilic drug (PED). Accordingly, our Specific Aims/Goals are – Aim/Goal 1. To screen for and characterize the neuroprotective effects of PEDs that activate the Nrf2/ARE transcriptional pathway in an in vitro model of oligomeric Aß-induced oxidative damage and neuroinflammation using hiPSC-derived cortical neurons and cerebral organoids. Aim/Goal 2. To determine the lead PED by assessing neuroprotective effects by neurobehavior and histology in vivo in AD transgenic mouse models (hAPP-J20 and 3x Tg mice) and optimize formulation of the lead. Toxicity testing will also be performed.

我们提出了一种通过Nrf2转录治疗阿尔茨海默病（AD）的新靶点和新药