Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice.
Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice.
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DOI：
10.1523/jneurosci.0616-08.2008
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发表时间：
2008-08-13
影响因子：
5.3
通讯作者：
El Khoury, Joseph
中科院分区：
文献类型：
--
作者：
Hickman, Suzanne E.;Allison, Elizabeth K.;El Khoury, Joseph
阿尔茨海默病（AD）中的早期小胶质细胞积聚通过在老年斑形成之前促进Aβ的清除来延缓疾病进展。然而，尽管小胶质细胞数量增加，但Aβ持续蓄积表明小胶质细胞清除Aβ的能力可能随着年龄和AD病理学进展而降低。为了确定衰老和Aβ沉积对小胶质细胞清除Aβ能力的影响，我们使用定量PCR分析了从1.5、3、8和14月龄转基因PS1-APP小鼠（一种已建立的AD小鼠模型）及其非转基因同窝仔新鲜分离的成年小胶质细胞中的基因表达。我们发现，与同窝对照组相比，老年PS1-APP小鼠的小胶质细胞（而非年轻小鼠）的Aβ结合清道夫受体SRA、CD 36和CD 38以及Aβ降解酶胰岛素溶酶、脑啡肽溶酶和MMP 9的表达降低了2-5倍。相比之下，PS1-APP小胶质细胞的促炎细胞因子IL-1β和TNFα增加了2.5倍，表明细胞因子产生与Aβ清除之间存在负相关性。为了支持这种可能性，我们发现培养的N9小鼠小胶质细胞与TNFα孵育降低了SRA和CD 36的表达，并减少了Aβ摄取。我们的数据表明，虽然早期小胶质细胞募集促进Aβ清除并在AD中具有神经保护作用，但随着疾病进展，响应Aβ沉积产生的促炎细胞因子下调参与Aβ清除的基因，并促进Aβ蓄积，因此有助于神经退行性变。AD的抗炎治疗应考虑小胶质细胞的这种二分法作用。
Early microglial accumulation in Alzheimer’s disease (AD) delays disease progression by promoting clearance of Aβ before formation of senile plaques. However, persistent Aβ accumulation in spite of increasing microglial numbers suggests that the ability of microglia to clear Aβ may decrease with age and progression of AD pathology. To determine the effects of aging and Aβ deposition on microglial ability to clear Aβ, we used quantitative PCR to analyze gene expression in freshly isolated adult microglia from 1.5, 3, 8 and 14 month-old transgenic PS1-APP mice, an established mouse model of AD, and from their non-transgenic littermates. We found that microglia from old PS1-APP mice, but not from younger mice, have a 2-5 fold decrease in expression of the Aβ-binding scavenger receptors SRA, CD36, and RAGE, and the Aβ-degrading enzymes insulysin, neprilysin and MMP9, compared to their littermate controls. In contrast, PS1-APP microglia had a 2.5 fold increase in the pro-inflammatory cytokines IL-1β and TNFα, suggesting that there is an inverse correlation between cytokine production and Aβ clearance. In support of this possibility, we found that incubation of cultured N9 mouse microglia with TNFα decreased the expression of SRA and CD36 and reduced Aβ uptake. Our data indicate that while early microglial recruitment promotes Aβ clearance and is neuroprotective in AD, as disease progresses, pro-inflammatory cytokines produced in response to Aβ deposition downregulate genes involved in Aβ clearance, and promote Aβ accumulation, therefore contributing to neurodegeneration. Anti-inflammatory therapy for AD should take this dichotomous microglial role into consideration.