Department of Veterinary Pathobiology, Texas A&M University, College Station, TX, USA.
J Neuroinflammation. 2010 Nov 16;7:78. doi: 10.1186/1742-2094-7-78.
Numerous studies have reported that increased expression of S100B, an intracellular Ca2+ receptor protein and secreted neuropeptide, exacerbates Alzheimer's disease (AD) pathology. However, the ability of S100B inhibitors to prevent/reverse AD histopathology remains controversial. This study examines the effect of S100B ablation on in vivo plaque load, gliosis and dystrophic neurons.
Because S100B-specific inhibitors are not available, genetic ablation was used to inhibit S100B function in the PSAPP AD mouse model. The PSAPP/S100B-/- line was generated by crossing PSAPP double transgenic males with S100B-/- females and maintained as PSAPP/S100B+/- crosses. Congo red staining was used to quantify plaque load, plaque number and plaque size in 6 month old PSAPP and PSAPP/S100B-/- littermates. The microglial marker Iba1 and astrocytic marker glial fibrillary acidic protein (GFAP) were used to quantify gliosis. Dystrophic neurons were detected with the phospho-tau antibody AT8. S100B immunohistochemistry was used to assess the spatial distribution of S100B in the PSAPP line.
PSAPP/S100B-/- mice exhibited a regionally selective decrease in cortical but not hippocampal plaque load when compared to PSAPP littermates. This regionally selective reduction in plaque load was accompanied by decreases in plaque number, GFAP-positive astrocytes, Iba1-positive microglia and phospho-tau positive dystrophic neurons. These effects were not attributable to regional variability in the distribution of S100B. Hippocampal and cortical S100B immunoreactivity in PSAPP mice was associated with plaques and co-localized with astrocytes and microglia.
Collectively, these data support S100B inhibition as a novel strategy for reducing cortical plaque load, gliosis and neuronal dysfunction in AD and suggest that both extracellular as well as intracellular S100B contribute to AD histopathology.
许多研究报告指出，S100B（一种细胞内 Ca2+ 受体蛋白和分泌神经肽）表达增加会加剧阿尔茨海默病（AD）的病理。然而，S100B 抑制剂预防/逆转 AD 组织病理学的能力仍存在争议。本研究探讨了 S100B 缺失对体内斑块负荷、神经胶质增生和退行性神经元的影响。
由于缺乏 S100B 特异性抑制剂，因此使用基因缺失来抑制 PSAPP AD 小鼠模型中的 S100B 功能。通过将 PSAPP 双转基因雄性与 S100B-/-雌性交配，生成 PSAPP/S100B-/-系，并维持为 PSAPP/S100B+/-杂交。用刚果红染色定量 6 月龄 PSAPP 和 PSAPP/S100B-/-同窝仔鼠的斑块负荷、斑块数量和斑块大小。用小胶质细胞标志物 Iba1 和星形胶质细胞标志物胶质纤维酸性蛋白（GFAP）定量神经胶质增生。用磷酸化 tau 抗体 AT8 检测退行性神经元。用 S100B 免疫组化评估 PSAPP 系中 S100B 的空间分布。
与 PSAPP 同窝仔鼠相比，PSAPP/S100B-/- 仔鼠皮质斑块负荷呈区域性选择性降低，但海马区无此变化。这种斑块负荷的区域性选择性降低伴随着斑块数量、GFAP 阳性星形胶质细胞、Iba1 阳性小胶质细胞和磷酸化 tau 阳性退行性神经元的减少。这些影响与 S100B 分布的区域性差异无关。PSAPP 仔鼠的海马和皮质 S100B 免疫反应与斑块相关，并与星形胶质细胞和小胶质细胞共定位。
综上所述，这些数据支持 S100B 抑制作为减少 AD 皮质斑块负荷、神经胶质增生和神经元功能障碍的新策略，并表明细胞外和细胞内的 S100B 均有助于 AD 组织病理学。
