Phenotypic and gene expression modification with normal brain aging in GFAP-positive astrocytes and neural stem cells.
Phenotypic and gene expression modification with normal brain aging in GFAP-positive astrocytes and neural stem cells.
复制标题
GFAP阳性星形胶质细胞和神经干细胞中正常脑老化的表型和基因表达修饰。
DOI：
10.1111/j.1474-9726.2011.00694.x
复制
发表时间：
2011-06
期刊：
影响因子：
7.8
通讯作者：
Peterson DA
中科院分区：
文献类型：
--
作者：
Bernal GM;Peterson DA
星形胶质细胞分泌的生长因子对局部环境既有神经保护作用又有支持作用。通过胶质原纤维酸性蛋白（GFAP）的表达，星形胶质细胞在不同成人脑区表现出形态、表型标志物和生长因子表达的异质性。在成人神经源性壁龛中，星形胶质细胞在神经源性壁龛中分泌血管内皮生长因子（VEGF）和成纤维细胞生长因子-2 (FGF-2)，也是特殊的gmap阳性多能神经干细胞（NSCs）的来源。正常的衰老伴随着中枢神经系统功能的下降和神经发生的减少。我们询问星形胶质细胞衍生因子的可用性降低是否可能导致与年龄相关的神经发生下降。确定衰老大脑中星形细胞活动的变化对于了解衰老过程中中枢神经系统的稳态和评估老年人群的适当治疗靶点至关重要。我们发现衰老大脑中GFAP、VEGF和FGF-2及其受体基因表达的区域特异性改变与星形胶质细胞反应性的变化相对应，支持星形胶质细胞的异质性，并证明了不同的衰老效应。我们发现gfap阳性的NSCs在年轻和老年海马中都独特地共表达VEGF及其关键的有丝分裂受体Flk-1，这表明可能存在自分泌/旁分泌信号传导机制。一旦NSCs成为神经元，VEGF的表达就会丧失，但flk -1介导的对VEGF信号的敏感性得以维持。我们认为，年龄相关的星形细胞变化导致VEGF和FGF-2信号传导减少，这反过来限制了神经干细胞和祖细胞的维持，并导致神经发生减少。
Astrocytes secrete growth factors that are both neuroprotective and supportive for the local environment. Identified by glial fibrillary acidic protein (GFAP) expression, astrocytes exhibit heterogeneity in morphology and in expression of phenotypic markers and growth factors throughout different adult brain regions. In adult neurogenic niches, astrocytes secrete vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) within the neurogenic niche, and are also a source of special GFAP-positive multipotent neural stem cells (NSCs). Normal aging is accompanied by a decline in CNS function and reduced neurogenesis. We asked if a decreased availability of astrocyte-derived factors may contribute to the age-related decline in neurogenesis. Determining alterations of astrocytic activity in the aging brain is crucial for understanding CNS homeostasis in aging and for assessing appropriate therapeutic targets for an aging population. We found region-specific alterations in gene expression of GFAP, VEGF and FGF-2 and their receptors in the aged brain corresponding to changes in astrocytic reactivity, supporting astrocytic heterogeneity and demonstrating a differential aging effect. We found that GFAP-positive NSCs uniquely coexpress both VEGF and its key mitotic receptor Flk-1 in both young and aged hippocampus, indicating a possible autocrine/paracrine signaling mechanism. VEGF expression is lost once NSCs commit to a neuronal fate, but Flk-1-mediated sensitivity to VEGF signaling is maintained. We propose that age-related astrocytic changes result in reduced VEGF and FGF-2 signaling, which in turn limits neural stem cell and progenitor cell maintenance and contributes to decreased neurogenesis.
登录
查看更多内容
影响因子：
25
作者：
Denise, A;Garcia, R;Sofroniew, MV
通讯作者：
Sofroniew, MV
影响因子：
18.2
作者：
Halassa MM;Haydon PG
通讯作者：
Haydon PG
影响因子：
--
作者：
Emsley, Jason G.;Macklis, Jeffrey D.
通讯作者：
Macklis, Jeffrey D.
影响因子：
3
作者：
Cansino, Selene
通讯作者：
Cansino, Selene
影响因子：
2.1
作者：
During, Matthew J.;Cao, Lei
通讯作者：
Cao, Lei