Department of Integrative Systems Neuroscience, West Point, PA, USA.
Exp Neurol. 2010 Jun;223(2):394-400. doi: 10.1016/j.expneurol.2009.09.001. Epub 2009 Sep 8.
Amyloid plaque deposition in the brain is a hallmark of Alzheimer's disease, but recent evidence indicates that the disease may be primarily caused by soluble amyloid-beta (1-42) (Abeta) oligomers or Abeta-derived diffusible ligands (ADDLs). ADDLs induce cognitive deficits in animal models and are thought to assemble in vitro by a mechanism apart from plaque formation. To investigate the in vivo relationship of ADDLs and plaques, biotin-labeled ADDLs (bADDLs) or amylin oligomers (bAMs) were injected into the hippocampus of hAPP overexpressing mice. The brains were collected 1 or 5 weeks after the last treatment and were processed for immunohistochemistry. Staining of tissue 1 week post-treatment showed bADDLs had diffused throughout the tissue and incorporated into plaques. Additionally, small deposits of thioflavin S-negative bADDLs were observed. At 5 weeks post-treatment, thioflavin S-positive material continued to accumulate around plaques containing bADDLs. Thioflavin S-positive material also accrued around bADDL deposits, implying that bADDLs were capable of seeding new plaques. In contrast, bAMs cleared from the brain and did not accumulate in plaques. Together, these data indicate that ADDLs are able to contribute to in vivo plaque formation in a peptide-specific manner.
脑内淀粉样斑块沉积是阿尔茨海默病的一个标志，但最近的证据表明，该疾病可能主要由可溶性淀粉样β（1-42）（Aβ）寡聚物或 Aβ衍生的可扩散配体（ADDLs）引起。ADDLs 在动物模型中诱导认知缺陷，并且据认为通过与斑块形成不同的机制在体外组装。为了研究 ADDLs 和斑块的体内关系，将生物素标记的 ADDLs（bADDLs）或淀粉样肽寡聚物（bAMs）注射到 hAPP 过表达小鼠的海马体中。最后一次处理后 1 或 5 周收集大脑，并进行免疫组织化学处理。组织处理后 1 周的染色显示 bADDLs 已扩散到整个组织中并掺入到斑块中。此外，还观察到少量硫黄素 S 阴性 bADDLs 沉积。在处理后 5 周时，含 bADDLs 的斑块周围继续积累硫黄素 S 阳性物质。硫黄素 S 阳性物质也在 bADDL 沉积周围积累，这意味着 bADDLs 能够引发新的斑块。相比之下，bAMs 从大脑中清除，并且不会在斑块中积累。这些数据表明，ADDLs 能够以肽特异性的方式促进体内斑块形成。
