Overexpression of human S100B exacerbates cerebral amyloidosis and gliosis in the Tg2576 mouse model of Alzheimer's disease.
Overexpression of human S100B exacerbates cerebral amyloidosis and gliosis in the Tg2576 mouse model of Alzheimer's disease.
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DOI：
10.1002/glia.20924
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发表时间：
2010-02
期刊：
影响因子：
6.2
通讯作者：
Town, Terrence
中科院分区：
文献类型：
--
作者：
Mori, Takashi;Koyama, Naoki;Arendash, Gary W.;Horikoshi-Sakuraba, Yuko;Tan, Jun;Town, Terrence
阿尔茨海默病（Alzheimer's disease，AD）是最常见的进行性痴呆，其病理特征是脑内淀粉样β（amyloid-β，Aβ）肽沉积形成老年斑。炎症和免疫反应途径在AD患者大脑中以低水平长期激活，并可能在疾病进展中发挥作用。与小胶质细胞一样，活化的星形胶质细胞在AD脑中产生许多急性期反应物和促炎分子。一种这样的分子S100 B在β-淀粉样蛋白沉积物附近的反应性星形胶质细胞中高度表达。我们以前已经表明，星形胶质细胞的增强和延长激活对神经元存活有不利影响。此外，我们已经暗示星形胶质细胞衍生的S100 B作为负责这种有害作用的候选分子。为了评估S100 B和AD发病机制之间的假定关系，我们将过表达人S100 B的转基因小鼠（ThuS 100 B小鼠）与AD的Tg 2576小鼠模型杂交，并检查AD样病理学。在双基因Tg 2576-huS 100 B小鼠中，脑实质和脑血管β-淀粉样蛋白沉积和Aβ水平增加。这些作用与淀粉样前体蛋白（APP）β-C-末端片段的裂解增加、N-末端APP裂解产物（可溶性APPβ）升高和β-位点APP裂解酶1激活相关。此外，双转基因小鼠表现出增强的反应性星形胶质细胞增生和小胶质细胞增生，高水平的S100表达，以及早在7-9个月大的促炎细胞因子水平的增加。这些结果提供了证据表明，（过）表达S100 B的行为，以加速AD样病理，并表明，抑制星形胶质细胞激活通过阻断S100 B的生物合成可能是一个有前途的治疗策略，以延迟AD的进展。
Alzheimer’s disease (AD) is the most common progressive dementia and is pathologically characterized by brain deposition of amyloid-β (Aβ) peptide as senile plaques. Inflammatory and immune response pathways are chronically activated in AD patient brains at low levels, and likely play a role in disease progression. Like microglia, activated astrocytes produce numerous acute-phase reactants and proinflammatory molecules in the AD brain. One such molecule, S100B, is highly expressed by reactive astrocytes in close vicinity of β-amyloid deposits. We have previously shown that augmented and prolonged activation of astrocytes has a detrimental impact on neuronal survival. Furthermore, we have implicated astrocyte-derived S100B as a candidate molecule responsible for this deleterious effect. To evaluate a putative relationship between S100B and AD pathogenesis, we crossed transgenic mice overexpressing human S100B (TghuS100B mice) with the Tg2576 mouse model of AD, and examined AD-like pathology. Brain parenchymal and cerebral vascular β-amyloid deposits and Aβ levels were increased in bigenic Tg2576-huS100B mice. These effects were associated with increased cleavage of the β-C-terminal fragment of amyloid precursor protein (APP), elevation of the N-terminal APP cleavage product (soluble APPβ), and activation of β-site APP cleaving enzyme 1. In addition, double transgenic mice showed augmented reactive astrocytosis and microgliosis, high levels of S100 expression, and increased levels of proinflammatory cytokines as early as 7-9 months of age. These results provide evidence that (over)-expression of S100B acts to accelerate AD-like pathology, and suggest that inhibiting astrocytic activation by blocking S100B biosynthesis may be a promising therapeutic strategy to delay AD progression.
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影响因子：
9.9
作者：
Mackenzie, IRA;Munoz, DG
通讯作者：
Munoz, DG
DOI：
10.1097/00004647-200206000-00010
发表时间：
2002-06-01
影响因子：
6.3
作者：
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通讯作者：
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影响因子：
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作者：
Ito, D;Tanaka, K;Fukuuchi, Y
通讯作者：
Fukuuchi, Y
影响因子：
4.2
作者：
Benzing, WC;Wujek, JR;Brunden, KR
通讯作者：
Brunden, KR
影响因子：
6.2
作者：
Hartlage-Rübsamen, M;Zeitschel, U;Rossner, S
通讯作者：
Rossner, S