Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aβ pathology.
Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aβ pathology.
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DOI：
10.1016/j.celrep.2021.109228
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发表时间：
2021-06-08
期刊：
影响因子：
8.8
通讯作者：
Gomez-Nicola D
中科院分区：
文献类型：
--
作者：
Hu Y;Fryatt GL;Ghorbani M;Obst J;Menassa DA;Martin-Estebane M;Muntslag TAO;Olmos-Alonso A;Guerrero-Carrasco M;Thomas D;Cragg MS;Gomez-Nicola D
小胶质细胞的持续增殖是阿尔茨海默病(AD)的一个关键标志，加速了其进展。在这里，我们旨在了解在AD中观察到的早期和长期的小胶质细胞增殖的长期影响，假设广泛和重复的循环将产生明显的转录和表型轨迹。我们表明，在类似AD的模型中看到的早期和持续的小胶质细胞增殖促进了复制性衰老，其特征是β-GAL活性增加，这是一个与衰老相关的转录信号，并且端粒缩短，这与人类死后AD病例中疾病相关小胶质细胞(DAM)和衰老的小胶质细胞的出现有关。阻止早期小胶质细胞的增殖阻碍衰老和DAM的发展，损害Aβ的积累，以及相关的神经元和突触损伤。总体而言，我们的结果表明，过度的小胶质细胞增殖导致衰老DAM的产生，这是AD早期Aβ病理的原因。在类阿尔茨海默病的病理中，部分小胶质细胞经历了复制性衰老，疾病相关小胶质细胞(DAM)表现出几种衰老的特征，防止增殖损害小胶质细胞衰老的发展，防止小胶质细胞衰老导致淀粉样变性和突触损伤减少等。显示在类似阿尔茨海默氏症的病理模型中，小胶质细胞经历了复制衰老。衰老在疾病相关的小胶质细胞中丰富，并由增殖周期的积累引起。预防小胶质细胞衰老导致病理减弱，突出了小胶质细胞与阿尔茨海默病早期阶段的联系。
The sustained proliferation of microglia is a key hallmark of Alzheimer’s disease (AD), accelerating its progression. Here, we aim to understand the long-term impact of the early and prolonged microglial proliferation observed in AD, hypothesizing that extensive and repeated cycling would engender a distinct transcriptional and phenotypic trajectory. We show that the early and sustained microglial proliferation seen in an AD-like model promotes replicative senescence, characterized by increased βgal activity, a senescence-associated transcriptional signature, and telomere shortening, correlating with the appearance of disease-associated microglia (DAM) and senescent microglial profiles in human post-mortem AD cases. The prevention of early microglial proliferation hinders the development of senescence and DAM, impairing the accumulation of Aβ, as well as associated neuritic and synaptic damage. Overall, our results indicate that excessive microglial proliferation leads to the generation of senescent DAM, which contributes to early Aβ pathology in AD. In Alzheimer’s-like pathology, a fraction of microglia undergo replicative senescence Disease-associated microglia (DAM) display several features of senescence Prevention of proliferation impairs the development of microglial senescence and DAMs Prevention of microglial senescence leads to reduced amyloidosis and synaptic damage Hu et al. show that microglia undergo replicative senescence in a model of Alzheimer’s-like pathology. Senescence is enriched in disease-associated microglia and is caused by the accumulation of proliferative cycles. Prevention of microglial senescence leads to diminished pathology, highlighting a link of microglia with the early stages of Alzheimer’s disease.
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耦合的增殖和凋亡维持成人大脑中小胶质细胞的快速离职。
影响因子：
8.8
作者：
Askew K;Li K;Olmos-Alonso A;Garcia-Moreno F;Liang Y;Richardson P;Tipton T;Chapman MA;Riecken K;Beccari S;Sierra A;Molnár Z;Cragg MS;Garaschuk O;Perry VH;Gomez-Nicola D
通讯作者：
Gomez-Nicola D
DOI：
10.1006/bbrc.1996.1112
发表时间：
1996-07-25
影响因子：
3.1
作者：
Imai, Y;Ibata, I;Kohsaka, S
通讯作者：
Kohsaka, S
影响因子：
14.9
作者：
Casella, Gabriel;Munk, Rachel;Gorospe, Myriam
通讯作者：
Gorospe, Myriam
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
DOI：
10.1007/978-1-62703-239-1_4
发表时间：
2013-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Carnero, Amancio
通讯作者：
Carnero, Amancio