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

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 随着我们的人口迅速老龄化，呈指数级增长。未能开发出有效药物的很大一部分原因 对AD患者来说是由于投入了不成比例的资源来追求 推测的治疗靶点与AD的淀粉样蛋白假说很大程度上不成功有关。只是最近才有 第一种基于抗淀粉样蛋白的疗法获得有条件的批准，许多主要的医疗中心正在衰落 由于对其安全性和有效性的严重担忧，将其提供给患者。因此，当务之急是我们 发现和开发AD的新的和互补的治疗靶点。众所周知，变老是最伟大的 阿尔茨海默病的危险因素，已有研究表明，脑烟酰胺腺嘌呤二核苷酸(NAD+)水平 随着年龄的增长，人的数量会减少，在AD时期更是如此。NAD+是一种重要的辅因子和能量代谢产物 大脑的健康和功能，我们假设保存大脑NAD+将预防、治疗，甚至可能 逆转临床前阿尔茨海默病小鼠模型中类似AD的病理和行为缺陷，被称为5xFAD小鼠。 重要的是，我们还表明，这种AD小鼠模型的特征是水平显著降低 大脑NAD+，从而对人类AD的这一重要方面进行建模。我们正在用以下工具检验我们的假设 一种新型的小分子化合物(P7C3-A20)，它能穿过血脑屏障，并有效地 选择性地刺激烟酰胺腺嘌呤核糖基转移酶(NAMPT)的活性。NAMPT为 NAD+合成限速酶和外周给药P7C3-A20可提高脑内NAD+水平 在疾病或受伤的情况下，否则会耗尽NAD+。P7C3-A20对小鼠肺损伤的保护作用 保存NAD+，从而阻止神经细胞退化已经在多种临床前模型中得到证实， 包括脑外伤、帕金森氏病和中风的小鼠模型，以及海马区的猴子模型 神经细胞死亡。延长每日服用P7C3-A20一年以上的时间没有显示出任何毒性或副作用 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 在每日口服9个月后进行系统检查。阿尔茨海默病的三个早期病理生理特征 取决于大脑中NAD+的可用性是轴突变性、血脑屏障恶化和过度 成年海马神经发生所致的幼年海马神经元高度死亡。我们建议 增加AD大脑中的NAD+水平将提供一种新的预防、治疗甚至甚至 颠倒公元。因此，我们将测试P7C3-A20治疗在早期疾病(治疗)中是否有效 2-6个月)、中期(6-12个月治疗)和晚期(12-12个月治疗) 雄性和雌性5xFAD小鼠)。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 阿尔茨海默病的病理特征，包括神经炎症、tau病理和淀粉样斑块聚集。我们 预测P7C3-A20将保持脑内NAD+水平，保护轴突结构，血脑屏障完整性，以及 在这些疾病的每个阶段，海马区的神经发生，这将与一般改善相关 认知和行为功能，以及减少对大脑的损害。如果是这样，那么我们的结果将确定 通过保存来预防、治疗和可能逆转AD的新方法的可靠的原则证明 大脑中正常的NAD+水平。重要的是，我们的结果也可以为未来的临床试验奠定基础。 一种目前正在开发药物的化合物(P7C3-A20)，以及一种脑神经细胞的血浆生物标志物 我们之前在小鼠和人类身上都建立了变性(乙酰化tau)。

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.