Nikolic William V, Hou Huayan, Town Terrence, Zhu Yuyan, Giunta Brian, Sanberg Cyndy D, Zeng Jin, Luo Deyan, Ehrhart Jared, Mori Takashi, Sanberg Paul R, Tan Jun
Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry & Behavioral Medicine, University of South Florida, Tampa, FL 33613, USA.
Stem Cells Dev. 2008 Jun;17(3):423-39. doi: 10.1089/scd.2008.0018.
Modulation of immune/inflammatory responses by diverse strategies including amyloid-beta (Abeta) immunization, nonsteroidal anti-inflammatory drugs, and manipulation of microglial activation states has been shown to reduce Alzheimer's disease (AD)-like pathology and cognitive deficits in AD transgenic mouse models. Human umbilical cord blood cells (HUCBCs) have unique immunomodulatory potential. We wished to test whether these cells might alter AD-like pathology after infusion into the PSAPP mouse model of AD. Here, we report a marked reduction in Abeta levels/beta-amyloid plaques and associated astrocytosis following multiple low-dose infusions of HUCBCs. HUCBC infusions also reduced cerebral vascular Abeta deposits in the Tg2576 AD mouse model. Interestingly, these effects were associated with suppression of the CD40-CD40L interaction, as evidenced by decreased circulating and brain soluble CD40L (sCD40L), elevated systemic immunoglobulin M (IgM) levels, attenuated CD40L-induced inflammatory responses, and reduced surface expression of CD40 on microglia. Importantly, deficiency in CD40 abolishes the effect of HUCBCs on elevated plasma Abeta levels. Moreover, microglia isolated from HUCBC-infused PSAPP mice demonstrated increased phagocytosis of Abeta. Furthermore, sera from HUCBC-infused PSAPP mice significantly increased microglial phagocytosis of the Abeta1-42 peptide while inhibiting interferon-gammainduced microglial CD40 expression. Increased microglial phagocytic activity in this scenario was inhibited by addition of recombinant CD40L protein. These data suggest that HUCBC infusion mitigates AD-like pathology by disrupting CD40L activity.
包括β-淀粉样蛋白（Aβ）免疫、非甾体抗炎药以及对小胶质细胞激活状态的调控等多种策略，已被证明可调节免疫/炎症反应，从而减轻阿尔茨海默病（AD）转基因小鼠模型中的AD样病理变化和认知缺陷。人脐带血细胞（HUCBCs）具有独特的免疫调节潜能。我们希望测试将这些细胞注入AD的PSAPP小鼠模型后是否会改变AD样病理变化。在此，我们报告多次低剂量注入HUCBCs后，Aβ水平/β-淀粉样斑块以及相关的星形细胞增生显著减少。HUCBC注入还减少了Tg2576 AD小鼠模型中的脑血管Aβ沉积。有趣的是，这些效应与CD40-CD40L相互作用的抑制有关，循环和脑可溶性CD40L（sCD40L）降低、全身免疫球蛋白M（IgM）水平升高、CD40L诱导的炎症反应减弱以及小胶质细胞表面CD40表达减少均证明了这一点。重要的是，CD40缺陷消除了HUCBCs对血浆Aβ水平升高的影响。此外，从注入HUCBC的PSAPP小鼠中分离出的小胶质细胞对Aβ的吞噬作用增强。此外，注入HUCBC的PSAPP小鼠的血清显著增加了小胶质细胞对Aβ1-42肽的吞噬作用，同时抑制了干扰素-γ诱导的小胶质细胞CD40表达。在这种情况下，添加重组CD40L蛋白可抑制小胶质细胞吞噬活性的增加。这些数据表明，注入HUCBCs通过破坏CD40L活性减轻AD样病理变化。
