Neuroinflammation and protein pathology in Parkinson's disease dementia.
Neuroinflammation and protein pathology in Parkinson's disease dementia.
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DOI：
10.1186/s40478-020-01083-5
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发表时间：
2020-12-03
影响因子：
7.1
通讯作者：
Williams-Gray CH
中科院分区：
文献类型：
--
作者：
Kouli A;Camacho M;Allinson K;Williams-Gray CH
帕金森病痴呆的神经病理学特征是α-突触核蛋白（路易体）在大脑边缘和新皮质区域聚集，并伴有阿尔茨海默病型病理。虽然免疫激活在帕金森病（PD）中得到了很好的描述，但它与蛋白质聚集的联系及其在PD痴呆中的作用尚未被探索。我们假设神经炎症过程是PDD病理的关键因素。为了验证这一假设，我们对17例无痴呆（pnd）的PD患者、11例PD痴呆（PDD）患者和14例年龄和性别匹配的神经健康对照者的死后7个大脑区域进行了检查。免疫组织化学染色后的数字定量显示，PDD患者海马、内嗅和枕颞皮质α-突触核蛋白病理程度明显高于pnd患者。相比之下，在任何检查区域，两组之间的tau或淀粉样蛋白-β病理都没有差异。重要的是，与对照组相比，我们发现痴呆PD脑杏仁核中激活的小胶质细胞增加，这与该区域α-突触核蛋白病理程度显著相关。与对照组相比，pnd和PDD患者在黑质和杏仁核均可见明显的CD4+ T淋巴细胞向脑实质浸润。在pnd /PDD病例中，杏仁核CD4+ T细胞计数与活化的小胶质细胞、α-突触核蛋白和tau病理相关。促炎细胞因子白介素1β在pnd /PDD患者的黑质和额叶皮层中也明显上调，与对照组相比，这些区域的toll样受体4 （TLR4）以及杏仁核也同时上调。本研究提供的证据表明，大脑边缘和皮质区域的免疫反应增加，包括小胶质细胞激活增加，T淋巴细胞浸润，促炎细胞因子和TLR基因表达上调，这在死后的PDD大脑中尚未报道。本文的在线版本（10.1186/s40478-020-01083-5）包含补充材料，仅供授权用户使用。
Parkinson’s disease dementia is neuropathologically characterized by aggregates of α-synuclein (Lewy bodies) in limbic and neocortical areas of the brain with additional involvement of Alzheimer’s disease-type pathology. Whilst immune activation is well-described in Parkinson’s disease (PD), how it links to protein aggregation and its role in PD dementia has not been explored. We hypothesized that neuroinflammatory processes are a critical contributor to the pathology of PDD. To address this hypothesis, we examined 7 brain regions at postmortem from 17 PD patients with no dementia (PDND), 11 patients with PD dementia (PDD), and 14 age and sex-matched neurologically healthy controls. Digital quantification after immunohistochemical staining showed a significant increase in the severity of α-synuclein pathology in the hippocampus, entorhinal and occipitotemporal cortex of PDD compared to PDND cases. In contrast, there was no difference in either tau or amyloid-β pathology between the groups in any of the examined regions. Importantly, we found an increase in activated microglia in the amygdala of demented PD brains compared to controls which correlated significantly with the extent of α-synuclein pathology in this region. Significant infiltration of CD4+ T lymphocytes into the brain parenchyma was commonly observed in PDND and PDD cases compared to controls, in both the substantia nigra and the amygdala. Amongst PDND/PDD cases, CD4+ T cell counts in the amygdala correlated with activated microglia, α-synuclein and tau pathology. Upregulation of the pro-inflammatory cytokine interleukin 1β was also evident in the substantia nigra as well as the frontal cortex in PDND/PDD versus controls with a concomitant upregulation in Toll-like receptor 4 (TLR4) in these regions, as well as the amygdala. The evidence presented in this study show an increased immune response in limbic and cortical brain regions, including increased microglial activation, infiltration of T lymphocytes, upregulation of pro-inflammatory cytokines and TLR gene expression, which has not been previously reported in the postmortem PDD brain. The online version of this article (10.1186/s40478-020-01083-5) contains supplementary material, which is available to authorized users.
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影响因子：
9.3
作者：
Cherry JD;Olschowka JA;O'Banion MK
通讯作者：
O'Banion MK
影响因子：
12.7
作者：
Halliday, Glenda;Hely, Mariese;Morris, John
通讯作者：
Morris, John
影响因子：
5.3
作者：
Fernández-Arjona MDM;Grondona JM;Granados-Durán P;Fernández-Llebrez P;López-Ávalos MD
通讯作者：
López-Ávalos MD
影响因子：
15.9
作者：
Brochard, Vanessa;Combadiere, Behazine;Hunot, Stephane
通讯作者：
Hunot, Stephane
DOI：
10.1016/j.jalz.2017.09.014
发表时间：
2018-03
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Ferman TJ;Aoki N;Crook JE;Murray ME;Graff-Radford NR;van Gerpen JA;Uitti RJ;Wszolek ZK;Graff-Radford J;Pedraza O;Kantarci K;Boeve BF;Dickson DW
通讯作者：
Dickson DW