HUCBC modulation of Alzheimer-like pathology and behavioral changes

描述（由申请人提供）：在阿尔茨海默病转基因小鼠模型中，通过多种不同的策略，包括A免疫、非甾体抗炎药（NSAID）给药和操纵小胶质细胞激活状态来调节炎症级联，都被证明可以减少阿尔茨海默病（AD）样病理和认知缺陷。我们最近的研究表明，在papp （APPswe, PSEN1dE9）小鼠中多次注射低剂量的Saneron人脐带血细胞单核分数（HUCBC，商标名“U-CORD-CELLTM”），一种众所周知的免疫调节剂，可以改善ad样病理。这是通过A?/?的显著降低观察到的。-淀粉样斑块和相关星形细胞病。与这种促炎信号的下调相一致，从hubc输注的papp小鼠中分离的培养小胶质细胞显示A？吞噬活性，从而清楚地证明了HUCBC潜在的免疫调节特性。尽管典型的大脑a ？斑块负担与认知改善有关，被认为是阿尔茨海默病改善的真正标志，我们的研究没有解决HUCBC注射相关的行为或认知改变。因此，在本提案中，我们想测试hubc输注是否可以促进papp小鼠行为和认知缺陷的恢复，并将这些变化与它们的病理改善联系起来。此外，我们还计划给这些小鼠注入人类成年单个核细胞，以证明HUCBC而不是成年单个核细胞的特定需求，以观察这些免疫调节和治疗作用。基于这些综合的证据线和我们最近的研究，我们假设多次低剂量注射U-CORD-CELL”到转基因papp小鼠将提供行为缺陷的拯救，这将与ad样病理的改善相关。本提案的目标是基于最近确定的Th1/Th2免疫、HUCBC移植和AD发病机制的作用，建立一个强大的、良好整合的研究项目。这一知识被用来合理化“U-CORD-CELL”作为一种潜在安全有效的AD免疫调节疗法。项目叙述-与公共卫生的相关性。综上所述，我们假设多次低剂量注射Saneron公司的人脐血细胞单核部分（HUCBC，商标名U-CORD-CELL）到转基因papp小鼠中，将提供行为缺陷的拯救，这将与ad样病理的改善相关。本提案的目标是基于最近确定的Th1/Th2免疫、HUCBC移植和AD发病机制的作用，建立一个强大的、良好整合的研究项目。这一知识被用来合理化“U-CORD-CELL”作为一种潜在安全有效的AD免疫调节疗法。

DESCRIPTION (provided by applicant): Modulation of the inflammatory cascade by several diverse strategies including A immunization, non-steroidal anti-inflammatory drug (NSAID) administration, and manipulation of microglial activation states have all been shown to reduce Alzheimer disease (AD)-like pathology, and cognitive deficits in AD transgenic mouse models. Our recent study demonstrated amelioration of AD-like pathology in PSAPP (APPswe, PSEN1dE9) mice when multiply injected with low dose of Saneron's human umbilical cord blood cells mononuclear fraction (HUCBC, trademark name "U-CORD-CELLTM"), a well known immunomodulator. This was observed through marked reduction of A?/?-amyloid plaques and associated astrocytosis. In concert with this down-regulation of pro-inflammatory signaling, cultured microglia isolated from HUCBC-infused PSAPP mice demonstrated increased A? phagocytic activity, thus clearly demonstrating HUCBC's potential immunomodulatory property. Although a typical reduction in cerebral A? plaque burden has been associated with an improvement in cognition, regarded as the true sign of improvement in AD, our study did not address either the behavioral or the cognitive changes associated with HUCBC injections. Thus, in this proposal we would like to test if HUCBC infusion can promote a rescue of behavioral and cognitive deficits and correlate these changes with their pathological improvements in PSAPP mice. Furthermore, we also plan to infuse these mice with human adult mononuclear fractions to demonstrate specific need for HUCBC rather than the adult mononuclear cells in order to observe these immunomodulatory and therapeutic effects. Based on these combined lines of evidence and our recent study, we hypothesize that multiple low dose injections of U-CORD-CELL" into transgenic PSAPP mice will provide a rescue of behavioral deficits, which will be correlated with improvements in AD-like pathology. The goal of this proposal is to establish a strong, well-integrated research program based on recently established roles of Th1/Th2 immunity, HUCBC transplantation, and AD pathogenesis. This knowledge is used to rationalize U-CORD-CELL" as a potentially safe and effective immunomodulatory therapy for AD.Project Narrative - Relevance to public health. In summary, we hypothesize that multiple low dose injections of Saneron's human umbilical cord blood cells mononuclear fraction (HUCBC, trademark name U-CORD-CELL") into transgenic PSAPP mice will provide a rescue of behavioral deficits, which will be correlated with improvements in AD-like pathology. The goal of this proposal is to establish a strong, well-integrated research program based on recently established roles of Th1/Th2 immunity, HUCBC transplantation, and AD pathogenesis. This knowledge is used to rationalize U-CORD-CELL" as a potentially safe and effective immunomodulatory therapy for AD.