Overexpression of Human S100B Exacerbates Cerebral Amyloidosis and Gliosis in the Tg2576 Mouse Model of Alzheimer's Disease

被引:161
作者
Mori, Takashi [1 ,2 ,3 ]
Koyama, Naoki [1 ,3 ]
Arendash, Gary W. [4 ]
Horikoshi-Sakuraba, Yuko [5 ]
Tan, Jun [6 ]
Town, Terrence [7 ,8 ,9 ]
机构
[1] Saitama Med Ctr, Dept Med Sci, Kawagoe, Saitama, Japan
[2] Saitama Med Ctr, Dept Pathol, Kawagoe, Saitama, Japan
[3] Univ Kawagoe, Kawagoe, Saitama, Japan
[4] Univ S Florida, Florida Alzheimers Dis Res Ctr, Tampa, FL USA
[5] Immunobiol Labs Co Ltd, Gunma, Japan
[6] Univ S Florida, Dept Psychiat & Behav Med, Tampa, FL USA
[7] Cedars Sinai Med Ctr, Maxine Dunitz Neurosurg Inst, Dept Neurosurg, Los Angeles, CA 90048 USA
[8] Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA
[9] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA
基金
日本学术振兴会;
关键词
S100B; astrocyte; microglia; amyloid-beta; inflammatory response; Alzheimer's transgenic mice; PERMANENT FOCAL ISCHEMIA; DELAYED INFARCT EXPANSION; ASTROCYTIC ACTIVATION; BRAIN-DAMAGE; BETA PROTEIN; PATHOLOGY; EXPRESSION; PLAQUES; INFLAMMATION; S100-BETA;
D O I
10.1002/glia.20924
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Alzheimer's disease (AD) is the most common progressive dementia and is pathologically characterized by brain deposition of amyloid-beta (A beta) 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 beta-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 beta-amyloid deposits and A beta levels were increased in bigenic Tg2576-huS100B mice. These effects were associated with increased cleavage of the beta-C-terminal fragment of amyloid precursor protein (APP), elevation of the N-terminal APP cleavage product (soluble APP beta), and activation of beta-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. (C) 2009 Wiley-Liss, Inc.
引用
收藏
页码:300 / 314
页数:15
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