Preservation of brain NAD+ as a novel non-amyloid based therapeutic strategy for Alzheimer’s disease

保留大脑 NAD 作为阿尔茨海默病的一种新型非淀粉样蛋白治疗策略

• 批准号: 10588414
• 负责人: ANDREW A PIEPER
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588414
• 关键词: Acceleration; Acetylation; Address; Adenine; Adult; Age; Age Months; Aging; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; American; Amyloid; Animals; Axon; Behavior; Behavioral; Biochemical; Biological Markers; Blood - brain barrier anatomy; Brain; Bromodeoxyuridine; Cessation of life; Chronic; Clinical Trials; Cognition; Cognitive; Congo Red; Deterioration; Disease; Enzymes; Extravasation; Failure; Female; Future; Glial Fibrillary Acidic Protein; Goals; Hematoxylin and Eosin Staining Method; Hippocampus; Human; Immunoglobulin G; Impaired cognition; Impairment; Injury; Length; Limb structure; Link; Measurement; Measures; Mediating; Medical center; Medicine; Mental Depression; Modeling; Monkeys; Mus; Nerve Block; Nerve Degeneration; Neurons; Niacinamide; Nicotinamide adenine dinucleotide; Oral Ingestion; Other Genetics; PDGFRB gene; PECAM1 gene; Parkinson Disease; Pathologic; Pathologic Processes; Pathology; Patient Care; Patients; Peptides; Pericytes; Peripheral; Persons; Plasma; Population; Pre-Clinical Model; Process; Resources; Safety; Senile Plaques; Silver Staining; Stains; Stroke; Structure; Symptoms; System; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Toxic effect; Transmission Electron Microscopy; Traumatic Brain Injury; Vacuole; Vascular Endothelial Cell; Veterans; Visualization; Work; aging population; anxiety-like behavior; axonal degeneration; blood-brain barrier crossing; blood-brain barrier function; body system; brain health; cofactor; cognitive function; cytokine; drug development; effective therapy; extracellular; fluoro jade; forced swim test; immunohistochemical markers; improved; male; morris water maze; mouse model; neurogenesis; neuroinflammation; neuron loss; neuropsychiatry; new therapeutic target; novel; novel strategies; novel therapeutics; object recognition; pharmacologic; pre-clinical; premature; preservation; prevent; protective effect; sarkosyl; side effect; small molecule; targeted treatment; tau Proteins; therapeutic target

Tragically, there is currently a lack of effective medicines to prevent, treat, or reverse AD, and the problem is growing exponentially as our population rapidly ages. A large part of the failure to develop effective medicines for patients with AD is due to the disproportionate amount of resources that have been devoted to pursuing putative therapeutic targets linked to the largely unsuccessful amyloid hypothesis of AD. Only very recently has the first anti-amyloid based therapy been conditionally approved, and many major medical centers are declining to offer this to patients due to serious concerns regarding its safety and efficacy. Thus, it is imperative that we discover and develop new and complementary therapeutic targets for AD. Aging is well known to be the greatest risk factor for AD, and it has been demonstrated that brain nicotinamide adenine dinucleotide (NAD+) levels decrease in people as they age, and even more so in AD. NAD+ is a critical cofactor and energy metabolite in brain health and function, and we hypothesize that preserving brain NAD+ will prevent, treat, and potentially even reverse AD-like pathology and behavioral deficits in a preclinical mouse model of AD, known as 5xFAD mice. Importantly, we have also shown that this mouse model of AD is characterized by significantly diminished levels of brain NAD+ as well, thereby modeling this important aspect of human AD. We are testing our hypothesis with a novel small molecule compound (P7C3-A20) that crosses the blood-brain barrier (BBB) and potently and selectively stimulates activity of nicotinamide adenine monophosphate ribosyltransferase (NAMPT). NAMPT is the rate limiting enzyme in NAD+ synthesis, and peripherally-administered P7C3-A20 elevates brain NAD+ levels under conditions of disease or injury that would otherwise deplete NAD+. The protective effect of P7C3-A20 to preserve NAD+ and thereby block nerve cell degeneration has been demonstrated in multiple preclinical models, including mouse models of TBI, Parkinson’s disease, and stroke, as well as a monkey model of hippocampal nerve cell death. Extended daily administration of P7C3-A20 upwards of a year has shown no toxicity or side effects in any animal system, including monkeys in which extensive pathological analysis across all organ systems was conducted after 9 months of daily oral ingestion. Three early pathophysiologic features of AD that are dependent on NAD+ availability in the brain are axonal degeneration, BBB deterioration, and excessively high death of young hippocampal neurons that arise from adult hippocampal neurogenesis. We propose that augmenting NAD+ levels in the AD brain will provide a novel means of preventing, treating, and potentially even reversing AD. We will thus test whether treatment with P7C3-A20 will be effective in early-disease (treatment from 2-6 months of age), mid-disease (treatment from 6-12 months of age), and late-disease (treatment from 12- 18 months of age) in both male and female 5xFAD mice. Protective effects in these domains will also be correlated with objective measure of cognitive and neuropsychiatric behavioral function, as well as other classical pathologic features of AD, including neuroinflammation, tau pathology, and amyloid plaque accumulation. We predict that P7C3-A20 will preserve brain NAD+ levels and protect axonal structure, BBB integrity, and hippocampal neurogenesis at each of these disease stages, which will be associated with generally improved cognitive and behavioral function, as well as reduced damage in the brain. If so, then our results will establish robust proof of principle for a novel approach to preventing, treating, and possibly reversing AD by preserving normal NAD+ levels in the brain. Importantly, our results could also establish a basis for future clinical trials with a compound currently in drug development (P7C3-A20), together with a plasma biomarker of brain nerve cell degeneration (acetylated-tau) that we have previously established in both mice and humans.

可悲的是，目前缺乏预防，治疗或反向广告的有效药物，问题是 随着我们人口的迅速增长，成倍增长。未能开发有效药物的很大一部分 对于AD的患者是由于专门用于追求的资源的数量不成比例 推定的理论针对与AD的主要不成功淀粉样假说相关的针对性。直到最近才有 有条件地批准了第一个基于抗淀粉样蛋白的治疗，许多主要的医疗中心正在下降 由于对患者的安全性和效率的严重担忧，将其提供给患者。那就是我们必须 发现并开发有关AD的新的和互补的治疗靶标。衰老是最大的 AD的危险因素，并且已经证明脑烟酰胺腺苷二核苷酸（NAD+）水平 随着年龄的增长，人们的年龄减少，甚至在AD中也会减少。 NAD+是关键的辅助因子和能量代谢物 大脑健康和功能，我们假设保存脑NAD+将阻止，治疗甚至可能 反向广告样的病理和行为形式在AD的临床前小鼠模型（称为5XFAD小鼠）中定义。 重要的是，我们还表明，该AD的小鼠模型的特征是水平明显降低 大脑nad+也是如此，从而对人类AD的这一重要方面进行建模。我们正在用 一种新型的小分子化合物（P7C3-A20），该化合物越过血脑屏障（BBB）以及潜在的以及 选择性刺激烟酰胺腺苷一磷酸核糖基转移酶（NAMPT）的活性。 Nampt是 NAD+合成中的速率限制酶，以及外围设施的P7C3-A20升高脑NAD+水平 在疾病或伤害的条件下，否则将缺少NAD+。 P7C3-A20的保护作用 保存nAD+，从而在多个临床前模型中证明了神经细胞变性， 包括TBI的小鼠模型，帕金森氏病和中风，以及海马模型 神经细胞死亡。每天延长P7C3-A20在一年以上的P7C3-A20都没有显示毒性或一面 在任何动物系统中的影响，包括猴子，其中所有器官的广泛病理分析 每日口服摄入9个月后进行系统。 AD的三个早期病理生理特征 依赖于大脑中的NAD+可用性是轴突发育，BBB定义，并且非常 由成年海马神经发生引起的年轻海马神经元的高死亡。我们提出了这一点 扩大广告大脑中的NAD+水平将提供一种新颖的方法，以防止，治疗甚至可能 反向广告。因此，我们将测试P7C3-A20治疗是否在早期疾病中有效（治疗） 从2-6个月大），中期（6-12个月的治疗）和晚期疾病（12-的治疗 雄性和雌性5XFAD小鼠的18个月大）。这些领域中的保护作用也将是 与认知和神经精神上的行为功能的客观测量以及其他经典相关 AD的病理特征，包括神经炎症，TAU病理学和淀粉样菌斑积累。我们 预测P7C3-A20将保持脑NAD+水平并保护轴突结构，BBB完整性和 在每个疾病阶段，海马神经发生，这将与普遍改善有关 认知和行为功能，以及大脑的损害减少。如果是这样，那么我们的结果将建立 通过保存来防止，治疗和可能逆转广告的新方法的原则证明 大脑中的正常NAD+水平。重要的是，我们的结果还可以为将来的临床试验建立基础 目前药物开发的化合物（P7C3-A20），以及脑神经细胞的血浆生物标志物 我们以前在小鼠和人类中都建立的变性（乙酰化-TAU）。