Hematopoietic Stem Cell Transplantation Combined with CSF1 Inhibition to Attenuate the Pathogenesis of Alzheimer's Disease

项目摘要 阿尔茨海默氏病（AD）是一种神经退行性疾病，其特征在于错误折叠的聚集蛋白（在阿尔茨海默氏病中）。 特别是淀粉样蛋白β和tau）和大脑先天免疫系统的慢性激活， 小胶质细胞或脑内巨噬细胞，它们调节神经变性。小神经胶质细胞的激活和 神经退行性变可能受载脂蛋白E（apoE）调节，小鼠研究表明apoE 缺失阻止小胶质细胞获得神经元细胞所需的神经退行性表型， 死亡其他小鼠研究表明，Pexidartinib（PLX，一种选择性CSF 1 R/c- 试剂盒/FLT 3抑制剂，其已显示容易穿过血脑屏障并消除小胶质细胞），可 在加速神经变性的apoE 4鼠模型中阻断神经变性和tau蛋白病。 小胶质细胞也可能受到异基因造血干细胞移植（HCT）的影响。虽然HCT 主要用于治疗造血和淋巴系统的恶性和非恶性疾病 系统，HCT前化疗和放疗，以去除供体造血系统， 受体造血系统的移植还具有诱导造血干细胞替代的间接作用。 受体小胶质细胞与供体小胶质细胞样细胞。因此，人们可以推断，APOE 4携带者， 代表迟发性AD最强的遗传风险因素，可能受益于疾病的替代， 小胶质细胞与来自健康供体的小胶质细胞样细胞（即APOE 2纯合子）通过以下组合 HCT和PLX（HCT+PLX）。与单独HCT不同，HCT+PLX可能需要6个月才能完全发挥作用， 在几周内完成小胶质细胞的更替。与单独使用PLX不同，HCT+PLX具有以下优点： 短期使用PLX（从而避免长期毒性，如血细胞减少或肝损伤）， 健康的供体小胶质细胞样细胞（vs.抑制）和潜在的永久治疗反应（“治愈”）。 我们建议验证HCT+PLX导致小胶质细胞完全更新和预防小胶质细胞增殖的假设。 在由co-I Sullivan开发的转基因tau/apoE 4小鼠模型中观察神经变性和tau蛋白病。的 P301 S Tau/APOE 4/4（TE 4）小鼠在6-10个月龄之间表现出显著的皮质萎缩，并且将用于 作为HCT的接受者。人apoE 2或apoE 4敲入小鼠将作为供体。终点包括 行为研究、Tau蛋白水平和小胶质细胞更新程度。积极的结果将奠定 为将这种新方法转化为人类HCT+PLX临床试验奠定了基础。

PROJECT SUMMARY Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by misfolded, aggregated proteins (in particular, amyloid beta and tau) and chronic activation of the brain’s innate immune system, especially microglia, or brain-resident macrophages, which modulate neurodegeneration. Microglia activation and neurodegeneration may be regulated by apolipoprotein E (apoE), with murine studies demonstrating that apoE deletion prevents microglia from acquiring a neurodegenerative phenotype that was required for neuronal cell death. Other murine studies have shown that microglial depletion by pexidartinib (PLX, a selective CSF1R/c- kit/FLT3 inhibitor that has been shown to readily cross the blood brain barrier and eliminate microglia), can block neurodegeneration and tauopathy in an apoE4 murine model of accelerated neurodegeneration. Microglia may also be affected by allogeneic hematopoietic stem cell transplantation (HCT). While HCT is predominantly performed to treat malignant and nonmalignant conditions of the hematopoietic and lymphatic systems, pre-HCT chemotherapy and radiation to remove the donor hematopoietic system and allow engraftment of the recipient hematopoietic system also has the indirect effect of inducing replacement of recipient microglia with donor microglia-like cells. Therefore, one could theorize that an APOE4 carrier, which represents the strongest genetic risk factor for late-onset AD, may benefit from replacement of diseased microglia with microglia-like cells from a healthy donor (i.e. APOE2 homozygote) through the combination of HCT and PLX (HCT+PLX). Unlike HCT alone, which could take 6 months for full effect, HCT+PLX may achieve microglial turnover in a matter of weeks. And unlike PLX alone, HCT+PLX has the advantages of short-term use of PLX (thus avoiding prolonged toxicities such as cytopenias or liver injury), reconstitution with healthy donor microglia-like cells (vs. suppression), and a potentially permanent treatment response (“cure”). We propose to test the hypothesis that HCT+PLX results in complete microglia turnover and prevention of neurodegeneration and tauopathy in a transgenic tau/apoE4 murine model developed by co-I Sullivan. The P301S Tau/APOE4/4 (TE4) mice exhibit dramatic cortical atrophy between 6-10 months of age and will serve as the recipients of HCT. Human apoE2 or apoE4 knock in mice will serve as donors. Endpoints include behavioral studies, Tau protein levels, and degree of microglial turnover. Positive results will lay the groundwork for translation of this novel approach to clinical trials of HCT+PLX in humans.