Neuroscience Laboratory, Department of Molecular Medicine, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, QC, Canada G1V 4G2.
Proc Natl Acad Sci U S A. 2013 Jan 29;110(5):1941-6. doi: 10.1073/pnas.1215165110. Epub 2013 Jan 15.
Alzheimer's disease (AD) is the most common cause of dementia worldwide. The pathogenesis of this neurodegenerative disease, currently without curative treatment, is associated with the accumulation of amyloid β (Aβ) in brain parenchyma and cerebral vasculature. AD patients are unable to clear this toxic peptide, leading to Aβ accumulation in their brains and, presumably, the pathology associated with this devastating disease. Compounds that stimulate the immune system to clear Aβ may therefore have great therapeutic potential in AD patients. Monophosphoryl lipid A (MPL) is an LPS-derived Toll-like receptor 4 agonist that exhibits unique immunomodulatory properties at doses that are nonpyrogenic. We show here that repeated systemic injections of MPL, but not LPS, significantly improved AD-related pathology in APP(swe)/PS1 mice. MPL treatment led to a significant reduction in Aβ load in the brain of these mice, as well as enhanced cognitive function. MPL induced a potent phagocytic response by microglia while triggering a moderate inflammatory reaction. Our data suggest that the Toll-like receptor 4 agonist MPL may be a treatment for AD.
阿尔茨海默病（AD）是全球最常见的痴呆症病因。这种神经退行性疾病的发病机制目前尚无治愈方法，与脑实质和脑血管中淀粉样β（Aβ）的积累有关。AD 患者无法清除这种毒性肽，导致 Aβ在其大脑中积累，推测与这种破坏性疾病相关的病理学。因此，刺激免疫系统清除 Aβ的化合物在 AD 患者中可能具有巨大的治疗潜力。单磷酰脂质 A（MPL）是一种 LPS 衍生的 Toll 样受体 4 激动剂，在非致热剂量下具有独特的免疫调节特性。我们在这里显示，重复全身注射 MPL，但不是 LPS，可显著改善 APP（swe）/PS1 小鼠的 AD 相关病理学。MPL 治疗导致这些小鼠大脑中的 Aβ负荷显著减少，并增强了认知功能。MPL 诱导小胶质细胞产生强烈的吞噬反应，同时引发适度的炎症反应。我们的数据表明，Toll 样受体 4 激动剂 MPL 可能是 AD 的一种治疗方法。
