Therapeutic targeting of TREM2 for Alzheimer's disease

摘要 确定阿尔茨海默病的新治疗靶点对于实现 国家阿尔茨海默氏症项目法(NAPA)规定，到2025年，有效的治疗措施到位。尽管有许多 临床前确定的治疗阿尔茨海默病的有希望的治疗方法，这些翻译 诊所的治疗方法令人难以置信地失望。大量的种群遗传学研究表明 已经为AD进行了治疗，这提供了一个机会来确定可以作为目标的疾病途径 从治疗上讲。一个对AD风险有很大影响的基因是髓系上表达的触发受体 细胞-2(TREM2)。顾名思义，TREM2是一种表达在小胶质细胞上的先天免疫受体，众所周知 通过DAP12发出信号以触发吞噬作用。TREM2 SNPs已被确定为显著增加 GWAS研究中AD的风险。这种风险增加的假设是，存在功能丧失、损害 天然免疫系统有效清除淀粉样蛋白沉积。我们假设以TREM2为目标 激活受体将调节神经炎性反应，并刺激小胶质细胞 吞噬细胞，清除淀粉样沉淀物。此外，我们假设激活TREM2 受体调节神经炎性反应将改善tau病理，提供 神经保护，并避免与Aβ靶向治疗相关的脑血管不良事件。至 激活TREM2受体，我们使用的是Alector，LLC，Alector-002a开发的抗体， 识别TREM2并激活受体。我们发现这种抗体具有免疫调节作用， 淀粉样蛋白沉积的清除，以及淀粉样蛋白沉积小鼠认知能力的改善。我们提出三个建议 具体目的是验证我们的假设： 具体目标1：确定A-002a的神经炎症、降低淀粉样蛋白和认知效应。 具体目标2：确定A-002a的tau修饰、神经保护和认知作用。 具体目标3：确定A-002a发生脑血管不良事件的可能性。

ABSTRACT The identification of novel therapeutic targets for Alzheimer's disease is necessary to reach the goal of the National Alzheimer's Project Act (NAPA) of having an effective treatment in place by 2025. Despite numerous promising therapeutic approaches identified pre-clinically to treat Alzheimer's disease, the translation of these therapies to the clinic have been incredibly disappointing. The vast number of population genetic studies that have been performed for AD present an opportunity to identify disease pathways what could be targeted therapeutically. One gene that has a strong effect on AD risk is the triggering receptor expressed on myeloid cells-2 (TREM2). As the name implies, TREM2, is an innate immune receptor expressed on microglia, known to signal through DAP12 to trigger phagocytosis. TREM2 SNPs have been identified as significantly increasing risk of AD in GWAS studies. The hypothesis for this increased risk is that there is a loss of function, impairing the innate immune system to clear amyloid deposition efficiently. We hypothesize that targeting TREM2 to activate the receptor will modulate the neuroinflammatory response and stimulate microglia to phagocytose and clear the amyloid deposits. Furthermore, we hypothesize that activating the TREM2 receptor to modulate the neuroinflammatory response will ameliorate tau pathology, provide neuroprotection, and avoid cerebrovascular adverse events associated with Aβ targeted therapies. To activate the TREM2 receptor, we are using an antibody developed by Alector, LLC, Alector-002a, that recognizes TREM2 and activates the receptor. We have found that the antibody show immune modulation, clearance of amyloid deposits, and cognitive improvement in amyloid depositing mice. We propose three specific aims to test our hypothesis: Specific Aim 1: Determine the neuroinflammatory, amyloid lowering and cognitive effects of A-002a. Specific Aim 2: Determine the tau modifying, neuroprotective and cognitive effects of A-002a. Specific Aim 3: Determine the potential for cerebrovascular adverse events of A-002a.