Zhu Yuyan, Hou Huayan, Nikolic William V, Ehrhart Jared, Rrapo Elona, Bickford Paula, Giunta Brian, Tan Jun
Rashid Laboratory Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry and Behavioral Medicine, University of South Florida College of Medicine, Tampa, Florida, United States of America.
PLoS One. 2008 May 14;3(5):e2135. doi: 10.1371/journal.pone.0002135.
Microglial activation, characterized by p38 MAPK or p44/42 MAPK pathway signal transduction, occurs in Alzheimer's disease (AD). Our previous studies demonstrated CD45, a membrane-bound protein tyrosine phosphatase (PTP), opposed beta-amyloid (Abeta) peptide-induced microglial activation via inhibition of p44/42 MAPK. Additionally we have shown agonism of the RB isoform of CD45 (CD45RB) abrogates lipopolysaccharide (LPS)-induced microglial activation.
In this study, CD45RB modulation of Abeta peptide or LPS-activated primary cultured microglial cells was further investigated. Microglial cells were co-treated with "aged" FITC-Abeta(1-42) and multiple CD45 isoform agonist antibodies. Data revealed cross-linking of CD45, particularly the CD45RB isoform, enhances microglial phagocytosis of Abeta(1-42) peptide and inhibits LPS-induced activation of p44/42 and p38 pathways. Co-treatment of microglial cells with agonist CD45 antibodies results in significant inhibition of LPS-induced microglial TNF-alpha and IL-6 release through p44/42 and/or p38 pathways. Moreover, inhibition of either of these pathways augmented CD45RB cross-linking induced microglial phagocytosis of Abeta(1-42) peptide. To investigate the mechanism(s) involved, microglial cells were co-treated with a PTP inhibitor (potassium bisperoxo [1,10-phenanthroline oxovanadate; Phen]) and Abeta(1-42) peptides. Data showed synergistic induction of microglial activation as evidenced by TNF-alpha and IL-6 release; both of which are demonstrated to be dependent on increased p44/42 and/or p38 activation. Finally, it was observed that cross-linking of CD45RB in the presence of Abeta(1-42) peptide, inhibits co-localization of microglial MHC class II and Abeta peptide; suggesting CD45 activation inhibits the antigen presenting phenotype of microglial cells.
In summary, p38 MAPK is another novel signaling pathway, besides p44/42, in which CD45RB cross-linking negatively regulates microglial Abeta phagocytosis while increasing potentially neurotoxic inflammation. Therefore, agonism of CD45RB PTP activity may be an effective therapeutic target for novel agents to treat AD due to its Abeta lowering, and inflammation reducing, properties that are particularly targeted at microglial cells. Such treatments may be more effective with less potential to produce systemic side-effects than therapeutics which induce non-specific, systemic down-regulation of inflammation.
以p38丝裂原活化蛋白激酶（MAPK）或p44/42 MAPK信号转导为特征的小胶质细胞活化发生在阿尔茨海默病（AD）中。我们之前的研究表明，CD45是一种膜结合蛋白酪氨酸磷酸酶（PTP），通过抑制p44/42 MAPK来对抗β-淀粉样蛋白（Aβ）肽诱导的小胶质细胞活化。此外，我们还表明CD45的RB同工型（CD45RB）激动剂可消除脂多糖（LPS）诱导的小胶质细胞活化。
在本研究中，进一步研究了CD45RB对Aβ肽或LPS激活的原代培养小胶质细胞的调节作用。小胶质细胞与“老化的”异硫氰酸荧光素（FITC）标记的Aβ（1-42）和多种CD45同工型激动剂抗体共同处理。数据显示，CD45，特别是CD45RB同工型的交联增强了小胶质细胞对Aβ（1-42）肽的吞噬作用，并抑制了LPS诱导的p44/42和p38信号通路的激活。小胶质细胞与激动剂CD45抗体共同处理可通过p44/42和/或p38信号通路显著抑制LPS诱导的小胶质细胞肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）的释放。此外，抑制这些信号通路中的任何一条均可增强CD45RB交联诱导的小胶质细胞对Aβ（1-42）肽的吞噬作用。为了研究其中涉及的机制，小胶质细胞与一种PTP抑制剂（双过氧[1,10-菲咯啉氧钒酸钾；Phen]）和Aβ（1-42）肽共同处理。数据显示，TNF-α和IL-6的释放证明了小胶质细胞活化的协同诱导；两者均被证明依赖于p44/42和/或p38激活的增加。最后，观察到在Aβ（1-42）肽存在的情况下CD45RB的交联抑制了小胶质细胞MHC II类分子与Aβ肽的共定位；这表明CD45激活抑制了小胶质细胞的抗原呈递表型。
总之，p38 MAPK是除p44/42之外的另一条新的信号通路，其中CD45RB交联在增加潜在神经毒性炎症的同时，对小胶质细胞Aβ吞噬作用产生负调节。因此，由于其降低Aβ和减轻炎症的特性，特别是针对小胶质细胞，CD45RB PTP活性激动剂可能是治疗AD新药的有效治疗靶点。与诱导非特异性全身炎症下调的治疗方法相比，这种治疗方法可能更有效，产生全身副作用的可能性更小。
