Microglial response to LPS increases in wild-type mice during aging but diminishes in an Alzheimer's mouse model: Implication of TLR4 signaling in disease progression.
Microglial response to LPS increases in wild-type mice during aging but diminishes in an Alzheimer's mouse model: Implication of TLR4 signaling in disease progression.
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DOI：
10.1016/j.bbrc.2016.09.073
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发表时间：
2016-10-14
影响因子：
3.1
通讯作者：
Fukuchi KI
中科院分区：
文献类型：
--
作者：
Go M;Kou J;Lim JE;Yang J;Fukuchi KI
小胶质细胞通过Toll样受体4（TLR 4）介导的β淀粉样蛋白（Aβ）清除可能在阿尔茨海默病（AD）的发病机制中发挥重要作用。然而，随着疾病的进展，活化的小胶质细胞似乎变得无法清除Aβ沉积物。由于反复暴露于TLR 4配体导致单核细胞/巨噬细胞对脂多糖（LPS）的反应减弱，并且聚集的Aβ是TLR 4配体，因此我们假设小胶质细胞长期暴露于Aβ沉积物可能诱导Toll样受体（TLR）信号传导功能障碍，导致Aβ清除率降低和疾病进展加速。在2月龄和12月龄Aβ沉积开始之前和之后，分别将LPS或磷酸盐缓冲盐水（PBS）注射到AD模型（TgAPP/PS1）和野生型（非Tg）小鼠的海马中。注射后7天收集脑标本，并分析小胶质细胞活化和Aβ负荷。注射LPS的2月龄非Tg小鼠在新皮质和海马中的Iba 1免疫反应性分别是注射PBS的小鼠的48倍和11倍，而注射LPS的2月龄TgAPP/PS1小鼠在新皮质和海马中分别增加了61倍和13倍。在2月龄时，LPS注射在TgAPP/PS1小鼠中比在非Tg小鼠中更强烈地激活小胶质细胞。相比之下，在12月龄时，注射LPS的非Tg小鼠的新皮质和海马中小胶质细胞的Iba 1免疫反应性分别增加了541倍和38倍，注射LPS的TgAPP/PS1小鼠的新皮质和海马中分别增加了2.7倍和3.3倍。令人惊讶的是，LPS注射降低了TgAPP/PS1小鼠的CD 45免疫反应性，但在12个月时增加了非Tg小鼠的CD 45免疫反应性。虽然12个月大的非Tg小鼠的小胶质细胞对LPS的反应比2个月大的非Tg小鼠更强，但TgAPP/PS1小鼠的小胶质细胞在衰老过程中对LPS的免疫反应减弱。我们的数据表明，小胶质细胞TLR 4信号在AD小鼠模型中发生了改变，并表明改变的TLR 4信号可能有助于Aβ在大脑中的蓄积。
Microglia-mediated clearance of amyloid beta-protein (Aβ) via Toll-like receptor 4 (TLR4) signaling may play an important role in the pathogenesis of Alzheimer’s disease (AD). However, as the disease progresses, activated microglia appear to become incapable of clearing Aβ deposits. Because repeated exposure to a TLR4 ligand leads to a diminished response of monocytes/macrophages to lipopolysaccharide (LPS) and because aggregated Aβ is a TLR4 ligand, we hypothesize that chronic exposure of microglia to Aβ deposits may induce a state of Toll-like receptor (TLR) signaling dysfunction, leading to decreased Aβ clearance and accelerated disease progression. LPS or phosphate-buffered saline (PBS) was injected into the hippocampus of AD-model (TgAPP/PS1) and wild-type (non-Tg) mice before and after the onset of Aβ deposition, at age 2 and 12 months, respectively. Brain specimens were collected 7 days post-injection and analyzed for microglial activation and Aβ load. While LPS-injected 2-month-old non-Tg mice showed 48-fold and 11-fold greater Iba1 immunoreactivity in the neocortex and hippocampus, respectively, compared with PBS-injected mice, LPS-injected 2-month-old TgAPP/PS1 mice had 61-fold and 13-fold increases in the neocortex and hippocampus, respectively. LPS injection activated microglia more strongly in TgAPP/PS1 mice than in non-Tg mice at 2 months of age. In contrast, at 12 months of age, Iba1 immunoreactivity of microglia was increased 541-fold and 38-fold in the neocortex and hippocampus, respectively, in LPS-injected non-Tg mice and 2.7-fold and 3.3-fold in the neocortex and hippocampus, respectively, in LPS-injected TgAPP/PS1 mice. Surprisingly, LPS injection decreased CD45 immunoreactivity in TgAPP/PS1 mice but increased it in non-Tg mice at 12 months. Although microglia in 12-month-old non-Tg mice showed stronger response to LPS than 2-month-old non-Tg mice, microglia in TgAPP/PS1 mice exhibited diminished immune response to LPS during aging. Our data indicate that microglial TLR4 signaling is altered in an AD mouse model and suggest that altered TLR4 signaling may contribute to Aβ accumulation in the brain.
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小胶质启动和对衰老中的继发性损伤的反应性增强，创伤性中枢神经系统损伤和神经退行性疾病。
影响因子：
4.7
作者：
Norden DM;Muccigrosso MM;Godbout JP
通讯作者：
Godbout JP
影响因子：
5.3
作者：
Hickman, Suzanne E.;Allison, Elizabeth K.;El Khoury, Joseph
通讯作者：
El Khoury, Joseph
影响因子：
4.4
作者：
Liu, Shirong;Liu, Yang;Fassbender, Klaus
通讯作者：
Fassbender, Klaus
影响因子：
6.1
作者：
McAlpine FE;Lee JK;Harms AS;Ruhn KA;Blurton-Jones M;Hong J;Das P;Golde TE;LaFerla FM;Oddo S;Blesch A;Tansey MG
通讯作者：
Tansey MG
DOI：
10.1523/jneurosci.5715-08.2009
发表时间：
2009-02-11
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Scholtzova H;Kascsak RJ;Bates KA;Boutajangout A;Kerr DJ;Meeker HC;Mehta PD;Spinner DS;Wisniewski T
通讯作者：
Wisniewski T