小胶质细胞促进阿尔茨海默病大脑中神经周细胞网络的丧失。
Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain.
机构信息
Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.
Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.
出版信息
EBioMedicine. 2020 Aug;58:102919. doi: 10.1016/j.ebiom.2020.102919. Epub 2020 Jul 31.
BACKGROUND
Microglia, the brain's principal immune cell, are increasingly implicated in Alzheimer's disease (AD), but the molecular interfaces through which these cells contribute to amyloid beta (Aβ)-related neurodegeneration are unclear. We recently identified microglial contributions to the homeostatic and disease-associated modulation of perineuronal nets (PNNs), extracellular matrix structures that enwrap and stabilize neuronal synapses, but whether PNNs are altered in AD remains controversial.
METHODS
Extensive histological analysis was performed on male and female 5xFAD mice at 4, 8, 12, and 18 months of age to assess plaque burden, microgliosis, and PNNs. Findings were validated in postmortem AD tissue. The role of neuroinflammation in PNN loss was investigated via LPS treatment, and the ability to prevent or rescue disease-related reductions in PNNs was assessed by treating 5xFAD and 3xTg-AD model mice with colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia.
FINDINGS
Utilizing the 5xFAD mouse model and human cortical tissue, we report that PNNs are extensively lost in AD in proportion to plaque burden. Activated microglia closely associate with and engulf damaged nets in the 5xFAD brain, and inclusions of PNN material are evident in mouse and human microglia, while aggrecan, a critical PNN component, deposits within human dense-core plaques. Disease-associated reductions in parvalbumin (PV)+ interneurons, frequently coated by PNNs, are preceded by PNN coverage and integrity impairments, and similar phenotypes are elicited in wild-type mice following microglial activation with LPS. Chronic pharmacological depletion of microglia prevents 5xFAD PNN loss, with similar results observed following depletion in aged 3xTg-AD mice, and this occurs despite plaque persistence.
INTERPRETATION
We conclude that phenotypically altered microglia facilitate plaque-dependent PNN loss in the AD brain.
FUNDING
The NIH (NIA, NINDS) and the Alzheimer's Association.
背景
小胶质细胞是大脑主要的免疫细胞，越来越多的研究表明其与阿尔茨海默病（AD）有关，但这些细胞参与淀粉样β（Aβ）相关神经退行性变的分子界面尚不清楚。我们最近发现小胶质细胞参与了周围神经网（PNNs）的稳态和疾病相关调节，PNNs 是一种包裹和稳定神经元突触的细胞外基质结构，但 AD 中 PNN 是否发生改变仍存在争议。
方法
在 4、8、12 和 18 个月大的雄性和雌性 5xFAD 小鼠中进行了广泛的组织学分析，以评估斑块负担、小胶质细胞增生和 PNNs。研究结果在 AD 死后组织中得到了验证。通过 LPS 处理研究了神经炎症在 PNN 丢失中的作用，并通过用集落刺激因子 1 受体（CSF1R）抑制剂 PLX5622 处理 5xFAD 和 3xTg-AD 模型小鼠来耗尽小胶质细胞，评估了预防或挽救疾病相关 PNNs 减少的能力。
结果
利用 5xFAD 小鼠模型和人皮质组织，我们报告说 PNNs 在 AD 中广泛丢失，与斑块负担成比例。激活的小胶质细胞与 5xFAD 大脑中受损的网络密切相关并吞噬它们，而 PNN 物质的包含物在小鼠和人类小胶质细胞中是明显的，而聚集蛋白聚糖，PNN 的一个关键成分，在人类致密核心斑块中沉积。与 PNN 经常覆盖的 PV+中间神经元相关的疾病相关减少，先于 PNN 覆盖和完整性受损，并且在 LPS 激活后，野生型小鼠中也出现了类似的表型。慢性药理学耗尽小胶质细胞可防止 5xFAD 的 PNN 丢失，在年龄较大的 3xTg-AD 小鼠中也观察到了类似的结果，尽管斑块持续存在。
结论
我们得出结论，表型改变的小胶质细胞促进了 AD 大脑中斑块依赖性 PNN 丢失。
资助
美国国立卫生研究院（NIA、NINDS）和阿尔茨海默病协会。
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