Astrocyte senescence as a component of Alzheimer's disease.
Astrocyte senescence as a component of Alzheimer's disease.
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DOI：
10.1371/journal.pone.0045069
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Torres C
中科院分区：
文献类型：
--
作者：
Bhat R;Crowe EP;Bitto A;Moh M;Katsetos CD;Garcia FU;Johnson FB;Trojanowski JQ;Sell C;Torres C
衰老是阿尔茨海默病（AD）的主要危险因素;然而，使大脑易患AD的衰老过程的方面在很大程度上是未知的。星形胶质细胞在中枢神经系统中执行无数功能以维持稳态并支持神经元功能。在体外，人类星形胶质细胞对氧化应激高度敏感，并在面临多种类型的应激时触发衰老程序。为了确定衰老的星形胶质细胞是否在体内出现，使用p16 INK 4a和基质金属蛋白酶-1（MMP-1）表达作为衰老的标志物来检查来自老年个体和AD患者的脑组织中衰老的星形胶质细胞的存在。与胎儿组织样本（n = 4）相比，在35至50岁（n = 6; P = 0.02）和78至90岁（n = 11; P<10−6）的受试者中观察到p16 INK 4a阳性星形胶质细胞显著增加。 此外，AD患者（n = 15）的额叶皮质中p16 INK 4a阳性星形胶质细胞的负荷显著高于年龄相似的非AD成人对照组（n = 25; P = 0.02）和胎儿对照组（n = 4; P<10−7）。 与p16 INK 4a阳性星形胶质细胞的衰老性质一致，金属蛋白酶MMP-1的增加与p16 INK 4a相关。在体外，β-淀粉样蛋白1-42（Aβ1-42）触发衰老，驱动p16 INK 4a和衰老相关β-半乳糖苷酶的表达。此外，我们发现衰老星形胶质细胞产生许多炎症细胞因子，包括白细胞介素-6（IL-6），这似乎是由p38 MAPK调节。我们认为p16 INK 4a阳性衰老星形胶质细胞的积累可能与年龄增加和散发性AD风险增加有关。
Aging is the main risk factor for Alzheimer’s disease (AD); however, the aspects of the aging process that predispose the brain to the development of AD are largely unknown. Astrocytes perform a myriad of functions in the central nervous system to maintain homeostasis and support neuronal function. In vitro, human astrocytes are highly sensitive to oxidative stress and trigger a senescence program when faced with multiple types of stress. In order to determine whether senescent astrocytes appear in vivo, brain tissue from aged individuals and patients with AD was examined for the presence of senescent astrocytes using p16INK4a and matrix metalloproteinase-1 (MMP-1) expression as markers of senescence. Compared with fetal tissue samples (n = 4), a significant increase in p16INK4a-positive astrocytes was observed in subjects aged 35 to 50 years (n = 6; P = 0.02) and 78 to 90 years (n = 11; P<10−6). In addition, the frontal cortex of AD patients (n = 15) harbored a significantly greater burden of p16INK4a-positive astrocytes compared with non-AD adult control subjects of similar ages (n = 25; P = 0.02) and fetal controls (n = 4; P<10−7). Consistent with the senescent nature of the p16INK4a-positive astrocytes, increased metalloproteinase MMP-1 correlated with p16INK4a. In vitro, beta-amyloid 1–42 (Aβ1–42) triggered senescence, driving the expression of p16INK4a and senescence-associated beta-galactosidase. In addition, we found that senescent astrocytes produce a number of inflammatory cytokines including interleukin-6 (IL-6), which seems to be regulated by p38MAPK. We propose that an accumulation of p16INK4a-positive senescent astrocytes may link increased age and increased risk for sporadic AD.
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DOI：
10.1186/alzrt5
发表时间：
2009-10-12
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Golde TE;Miller VM
通讯作者：
Miller VM
影响因子：
13.6
作者：
Freund A;Orjalo AV;Desprez PY;Campisi J
通讯作者：
Campisi J
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：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
影响因子：
5.3
作者：
Abramov, AY;Canevari, L;Duchen, MR
通讯作者：
Duchen, MR