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，目前缺乏有效的药物来预防，治疗或逆转AD，问题是 随着人口迅速老龄化，人口呈指数级增长。很大一部分原因是未能开发出有效的药物 对于AD患者来说，这是由于投入了不成比例的资源， 与AD的淀粉样蛋白假说基本上不成功有关的假定治疗靶点。直到最近， 第一个基于抗淀粉样蛋白的治疗获得了有条件的批准，许多主要的医疗中心正在下降， 由于对它的安全性和有效性的严重担忧，因此，我们必须 发现和开发新的和互补的治疗AD的目标。众所周知，衰老是最大的 AD的危险因素，并且已经证明脑中的烟酰胺腺嘌呤二核苷酸（NAD+）水平 随着年龄的增长，人的寿命会减少，而AD的情况更是如此。NAD+是一种关键的辅因子和能量代谢产物， 大脑健康和功能，我们假设，保留大脑NAD+将预防，治疗，甚至可能 逆转AD临床前小鼠模型（称为5xFAD小鼠）中的AD样病理和行为缺陷。 重要的是，我们还表明，这种AD小鼠模型的特征是， 大脑NAD+的水平，从而模拟人类AD的这一重要方面。我们正在测试我们的假设， 一种新的小分子化合物（P7 C3-A20），其穿过血脑屏障（BBB）并有效地 选择性刺激烟酰胺腺嘌呤一磷酸核糖基转移酶（NAMPT）的活性。NAMPT是 NAD+合成中的限速酶和外周给药的P7 C3-A20升高脑NAD+水平 在疾病或损伤的条件下，否则会耗尽NAD+。P7 C3-A20对大鼠脑缺血再灌注损伤的保护作用 保存NAD+并由此阻断神经细胞变性已经在多个临床前模型中得到证实， 包括TBI，帕金森病和中风的小鼠模型，以及海马神经元的猴模型。 神经细胞死亡P7 C3-A20的每日给药延长一年以上，没有显示出毒性或副作用。 对任何动物系统的影响，包括对所有器官进行广泛病理分析的猴子 系统进行了9个月后，每天口服摄入。AD的三个早期病理生理特征， 依赖于脑中NAD+可用性的是轴突变性、BBB恶化和过度 由成年海马神经发生引起的年轻海马神经元的高死亡率。我们建议 增加AD大脑中的NAD+水平将提供一种预防、治疗甚至潜在治疗AD的新方法。 反AD因此，我们将测试用P7 C3-A20治疗是否在早期疾病（治疗）中有效。 从2-6个月大）、中期疾病（从6-12个月大治疗）和晚期疾病（从12- 14个月大治疗）。 18月龄）。在这些领域的保护作用也将是 与认知和神经精神行为功能的客观测量以及其他经典的 AD的病理学特征，包括神经炎症、tau病理学和淀粉样斑块积累。我们 预测P7 C3-A20将保持脑NAD+水平并保护轴突结构、BBB完整性， 海马神经发生在这些疾病的每个阶段，这将与一般改善 认知和行为功能，以及减少大脑损伤。如果是这样，那么我们的结果将建立 一种新的预防、治疗和可能逆转AD的方法， 大脑中的NAD+水平正常。重要的是，我们的结果也可以为未来的临床试验奠定基础， 目前正在药物开发中的化合物（P7 C3-A20），以及脑神经细胞的血浆生物标志物 变性（乙酰化-tau），这是我们先前在小鼠和人类中建立的。