Development of Novel Therapeutics for the Treatment of Alzheimer's Disease

阿尔茨海默病（AD）是痴呆症的最常见原因，并且是老年人的第六大死亡原因。 美国的今天有超过580万人患有AD，预计到2050年， 近1 400万人将受到这一毁灭性疾病的影响。美洲印第安人和阿拉斯加原住民 (AI/AN）社区，AD和相关痴呆症（ADRD）的影响可能会产生更大的影响 因为与AD/ADRD相关的风险因素的患病率较高。事实上， 预计到2060年痴呆症患者人数将增长五倍以上。老年AI/AN成年人数量的增加 痴呆症患者的生活将对整个社区的活力产生重大和有害的影响。为了 为了解决这一流行病，需要新的治疗方法来靶向与AD/ADRD相关的特定途径 发病机制例如，大量的研究表明，神经炎症在神经系统中起着积极的作用。 在AD发病机制中的作用，以及小胶质细胞通过细胞-蛋白质结合可溶性淀粉样蛋白β（Aβ）寡聚体和Aβ纤维。 表面甲酰基肽受体2（FPR 2），导致炎症反应。因此，我们假设， 靶向和破坏小胶质细胞活化途径和炎性细胞因子的特异性治疗剂 极化可以中断有助于AD发病机制的有害炎症事件， 一种解决炎症的小胶质细胞M2极化。 我们建议通过描述人类小胶质细胞的炎症反应来解决这一假设 由可溶性和聚集性Aβ诱导，包括细胞内Ca 2+通量、活性氧（ROS） 产生、细胞因子/趋化因子产生和核因子κB（NF-κB）活化。我们还将描述 Aβ诱导的小胶质细胞炎症表型转换（M1/M2）和基因表达（RNA-Seq） activation.然后，我们将评估新型小分子FPR 2拮抗剂对人小胶质细胞的作用， 炎症反应，以确定哪些化合物是有效的炎症抑制剂， 小胶质细胞M2极化。多年来，我们已经发现了大量的FPR 2配体，包括一些 一些对FPR 2具有特异性，一些对FPR 1/FPR 2具有混合受体特异性，其可偏向FPR 2。 该FPR 2配体文库将用于初始筛选，但随后将进行结构-活性关系 (SAR)分析、分子建模和新类似物的获取/合成。 这些临床前研究的完成将导致一类新的药物的开发， 可以开发用于治疗AD/ADRD的前瞻性化合物，其可以 对AI/AN社区有很大的好处。这显然是一个创新的方法来治疗一个流行的 这种疾病几乎没有有效的药物。该提案还将解决有关的重大知识差距， 淀粉样肽诱导的小胶质细胞炎症的机制。在动物模型中的进一步测试 并将在未来的提案中寻求最有前途的候选FPR 2配体的开发。

Alzheimer’s disease (AD) is the most common cause of dementia and is the sixth leading cause of death in the United States. More than 5.8 million people live with AD today, and it is projected that by the year 2050, nearly 14 million people will be affected by this devastating disease. For American Indian and Alaska Native (AI/AN) communities, the effects of AD and related dementias (ADRD) will likely have an even greater impact because of the higher prevalence of risk factors associated with AD/ADRD. Indeed, the number of AI/ANs living with dementia is projected to grow over five-fold by 2060. This increase in the number of older AI/AN adults living with dementia will have a significant and detrimental impact on the vitality of whole communities. In order to address this epidemic, new therapeutics are needed that target specific pathways associated with AD/ADRD pathogenesis. For example, a significant amount of research suggests that neuroinflammation plays an active role in AD pathogenesis and that microglial cells bind to soluble amyloid β (Aβ) oligomers and Aβ fibrils via cell- surface formyl peptide receptor 2 (FPR2), resulting in an inflammatory response. Thus, we hypothesize that specific therapeutics that target and disrupt microglial cell activation pathways and inflammatory polarization could interrupt the harmful inflammatory events contributing to AD pathogenesis and favor a microglial M2 polarization that resolves inflammation. We propose to address this hypothesis by characterizing the human microglial inflammatory responses induced by soluble and aggregated Aβ, including intracellular Ca2+ flux, reactive oxygen species (ROS) production, cytokine/chemokine production, and nuclear factor κB (NF-κB) activation. We will also characterize microglial inflammatory phenotype switching (M1/M2) and gene expression (RNA-Seq) in response to Aβ activation. We will then evaluate effects of novel small molecule FPR2 antagonists on human microglial cell inflammatory responses to determine which compounds are effective inhibitors of inflammation and can enhance microglial M2 polarization. We have discovered a large number of FPR2 ligands over the years, including some specific for FPR2 and some with mixed receptor specificity for FPR1/FPR2, which can be biased towards FPR2. This library of FPR2 ligands will be useful for initial screening but will be followed by structure-activity relationship (SAR) analysis, molecular modeling, and acquisition/synthesis of new analogs. The accomplishment of these preclinical studies will lead to the development of a new class of prospective compounds that could be developed for the treatment of AD/ADRD, which could significantly benefit the AI/AN Communities. This is clearly an innovative approach to treating a prevalent disease where there are few effective drugs. The proposal will also address significant knowledge gaps relevant to the mechanisms of microglial inflammation induced by amyloid peptides. Further testing in an animal model and development of the most promising candidate FPR2 ligands will be pursued in a future proposal.