Tau oligomer induced HMGB1 release contributes to cellular senescence and neuropathology linked to Alzheimer's disease and frontotemporal dementia.
Tau oligomer induced HMGB1 release contributes to cellular senescence and neuropathology linked to Alzheimer's disease and frontotemporal dementia.
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DOI：
10.1016/j.celrep.2021.109419
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发表时间：
2021-07-20
期刊：
影响因子：
8.8
通讯作者：
Kayed R
中科院分区：
文献类型：
--
作者：
Gaikwad S;Puangmalai N;Bittar A;Montalbano M;Garcia S;McAllen S;Bhatt N;Sonawane M;Sengupta U;Kayed R
脑中的衰老、病理性tau寡聚体（TauO）和慢性炎症在包括阿尔茨海默病（AD）和额颞叶痴呆（FTD）在内的tau蛋白病中起核心作用。然而，TauO诱导的衰老相关神经炎症的潜在机制仍不清楚。在这里，我们表明，TauO相关的星形胶质细胞显示出衰老样表型在AD和FTD患者的大脑。TauO暴露通过高迁移率族蛋白1（HMGB 1）释放和炎性衰老相关分泌表型（SASP）触发星形胶质细胞衰老，其介导邻近细胞中的旁分泌衰老。使用丙酮酸乙酯（EP）和甘草酸（GA）的HMGB 1释放抑制通过抑制p38-丝裂原活化蛋白激酶（MAPK）和核因子κB（NF-κB）-SASP发展的基本信号传导途径来防止TauO诱导的衰老。尽管在12个月大的hTau小鼠中发生了tau蛋白病，但EP+GA治疗显著降低了脑中的TauO和衰老细胞负荷，减少了神经炎症，从而改善了认知功能。总的来说，TauO诱导的HMGB 1释放促进细胞衰老和神经病理学，这可能代表了包括AD和FTD在内的tau蛋白病的重要共同病理机制。Gaikwad et al.证明了TauO相关星形胶质细胞在AD和FTD患者的脑中表现出衰老样表型。他们发现HMGB 1释放是TauO诱导的细胞衰老、tau蛋白病进展和认知缺陷的关键事件，这表明HMGB 1释放可能代表tau蛋白病中重要的共同病理机制。
Aging, pathological tau oligomers (TauO), and chronic inflammation in the brain play a central role in tauopathies, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD). However, the underlying mechanism of TauO-induced aging-related neuroinflammation remains unclear. Here, we show that TauO-associated astrocytes display a senescence-like phenotype in the brains of patients with AD and FTD. TauO exposure triggers astrocyte senescence through high mobility group box 1 (HMGB1) release and inflammatory senescence-associated secretory phenotype (SASP), which mediates paracrine senescence in adjacent cells. HMGB1 release inhibition using ethyl pyruvate (EP) and glycyrrhizic acid (GA) prevents TauO-induced senescence through inhibition of p38-mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB)—the essential signaling pathways for SASP development. Despite the developed tauopathy in 12-month-old hTau mice, EP+GA treatment significantly decreases TauO and senescent cell loads in the brain, reduces neuroinflammation, and thus ameliorates cognitive functions. Collectively, TauO-induced HMGB1 release promotes cellular senescence and neuropathology, which could represent an important common pathomechanism in tauopathies including AD and FTD. Gaikwad et al. demonstrate that TauO-associated astrocytes exhibit senescence-like phenotype in the brain of patients with AD and FTD. They find that HMGB1 release is a crucial event for TauO-induced cellular senescence, tauopathy progression, and cognitive deficits, indicating that HMGB1 release could represent an important common pathomechanism in tauopathies.
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影响因子：
30.8
作者：
Calogero, S;Grassi, F;Bianchi, ME
通讯作者：
Bianchi, ME
影响因子：
4.6
作者：
Fujita K;Motoki K;Tagawa K;Chen X;Hama H;Nakajima K;Homma H;Tamura T;Watanabe H;Katsuno M;Matsumi C;Kajikawa M;Saito T;Saido T;Sobue G;Miyawaki A;Okazawa H
通讯作者：
Okazawa H
DOI：
10.1053/j.jvca.2008.08.005
发表时间：
2009-06-01
影响因子：
2.8
作者：
Bennett-Guerrero, Elliott;Swaminathan, Madhav;Fink, Mitchell P.
通讯作者：
Fink, Mitchell P.
影响因子：
5.3
作者：
Fakhoury M
通讯作者：
Fakhoury M
来自小鼠大脑多个区域的老化星形胶质细胞转录组。
影响因子：
8.8
作者：
Boisvert MM;Erikson GA;Shokhirev MN;Allen NJ
通讯作者：
Allen NJ