Hyperactivation of monocytes and macrophages in MCI patients contributes to the progression of Alzheimer's disease.
Hyperactivation of monocytes and macrophages in MCI patients contributes to the progression of Alzheimer's disease.
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DOI：
10.1186/s12979-021-00236-x
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发表时间：
2021-06-21
期刊：
影响因子：
--
通讯作者：
Fulop T
中科院分区：
文献类型：
--
作者：
Munawara U;Catanzaro M;Xu W;Tan C;Hirokawa K;Bosco N;Dumoulin D;Khalil A;Larbi A;Lévesque S;Ramassamy C;Barron AE;Cunnane S;Beauregard PB;Bellenger JP;Rodrigues S;Desroches M;Witkowski JM;Laurent B;Frost EH;Fulop T
阿尔茨海默病（AD）是最常见的神经退行性疾病，最终表现为临床痴呆。尽管付出了大量的努力和充足的实验数据，但神经炎症在全身炎症中的作用仍然不确定。虽然小胶质细胞的影响是公认的，外周单核细胞/巨噬细胞的确切贡献仍然是未知的，特别是关于他们在AD的各个阶段的作用。AD发展数十年，其临床表现之前是主观记忆障碍（SMC）和轻度认知障碍（MCI）;因此，问题是外周先天免疫应答如何随着疾病的进展而变化。因此，为了进一步研究单核细胞/巨噬细胞在AD进展中的作用，我们评估了SMC、MCI和AD阶段患者的表型和功能，并将其与认知健康对照进行比较。我们还概念化了一个理想化的数学模型来解释单核细胞/巨噬细胞沿着疾病进展的功能。我们发现，随着疾病的进展，单核细胞和巨噬细胞群体有明显的表型和功能变化。在SMC患者的单核细胞中已经观察到刺激后产生更高的自由基。最引人注目的结果表明，在MCI组中，在疾病的前驱期，外周单核细胞的活化（过度活化）是最强的。单核细胞表现出显着增加的趋化性，自由基的产生，和细胞因子的产生响应TLR 2和TLR 4刺激。我们的数据表明，外周先天免疫系统激活的过程中，从SMC通过MCI到AD，与最高水平的激活是在MCI受试者和最低的AD患者。其中一些参数可作为生物标志物，但需要进行更多的整体免疫研究，以找到疾病的最佳时期进行临床干预。在线版本包含补充材料，可通过10.1186/s12979-021-00236-x获得。
Alzheimer’s disease (AD) is the most common neurodegenerative disease ultimately manifesting as clinical dementia. Despite considerable effort and ample experimental data, the role of neuroinflammation related to systemic inflammation is still unsettled. While the implication of microglia is well recognized, the exact contribution of peripheral monocytes/macrophages is still largely unknown, especially concerning their role in the various stages of AD. AD develops over decades and its clinical manifestation is preceded by subjective memory complaints (SMC) and mild cognitive impairment (MCI); thus, the question arises how the peripheral innate immune response changes with the progression of the disease. Therefore, to further investigate the roles of monocytes/macrophages in the progression of AD we assessed their phenotypes and functions in patients at SMC, MCI and AD stages and compared them with cognitively healthy controls. We also conceptualised an idealised mathematical model to explain the functionality of monocytes/macrophages along the progression of the disease. We show that there are distinct phenotypic and functional changes in monocyte and macrophage populations as the disease progresses. Higher free radical production upon stimulation could already be observed for the monocytes of SMC patients. The most striking results show that activation of peripheral monocytes (hyperactivation) is the strongest in the MCI group, at the prodromal stage of the disease. Monocytes exhibit significantly increased chemotaxis, free radical production, and cytokine production in response to TLR2 and TLR4 stimulation. Our data suggest that the peripheral innate immune system is activated during the progression from SMC through MCI to AD, with the highest levels of activation being in MCI subjects and the lowest in AD patients. Some of these parameters may be used as biomarkers, but more holistic immune studies are needed to find the best period of the disease for clinical intervention. The online version contains supplementary material available at 10.1186/s12979-021-00236-x.
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DOI：
10.3233/jad-179901
发表时间：
2018
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Cummings J;Ritter A;Zhong K
通讯作者：
Zhong K
DOI：
10.1096/fj.201600677rr
发表时间：
2017-01
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
--
作者：
Famenini S;Rigali EA;Olivera-Perez HM;Dang J;Chang MT;Halder R;Rao RV;Pellegrini M;Porter V;Bredesen D;Fiala M
通讯作者：
Fiala M
影响因子：
4
作者：
Bourgade, Karine;Le Page, Aurelie;Fueloep, Tamas, Jr.
通讯作者：
Fueloep, Tamas, Jr.
DOI：
10.1046/j.1365-2362.2002.00994.x
发表时间：
2002-05-01
影响因子：
5.5
作者：
Fiala, M;Liu, QN;Vinters, HV
通讯作者：
Vinters, HV
DOI：
10.1093/infdis/jiz692
发表时间：
2020-11-09
期刊：
The Journal of infectious diseases
影响因子：
--
作者：
Ciarlo E;Heinonen T;Théroude C;Asgari F;Le Roy D;Netea MG;Roger T
通讯作者：
Roger T