Microglial response to increasing amyloid load saturates with aging: a longitudinal dual tracer in vivo μPET-study.
Microglial response to increasing amyloid load saturates with aging: a longitudinal dual tracer in vivo μPET-study.
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DOI：
10.1186/s12974-018-1347-6
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发表时间：
2018-11-06
影响因子：
9.3
通讯作者：
Brendel M
中科院分区：
文献类型：
--
作者：
Blume T;Focke C;Peters F;Deussing M;Albert NL;Lindner S;Gildehaus FJ;von Ungern-Sternberg B;Ozmen L;Baumann K;Bartenstein P;Rominger A;Herms J;Brendel M
阿尔茨海默病（AD）进展过程中小胶质细胞活化和β-淀粉样蛋白（Aβ）积累之间的因果关系仍然存在争议。因此，我们使用纵向双示踪剂体内小动物正电子发射断层扫描（μPET）成像来解析Aβ小鼠模型老化过程中Aβ沉积与小胶质细胞反应之间相关性的进展。使用Aβ（18 F-florbetaben）和18 kDa转运蛋白（TSPO）μPET（18 F-GE 180）纵向研究APP-SL 70小鼠（N = 17;基线年龄3.2-8.5个月）和年龄匹配的C57 B1/6对照（野生型（wt））6个月。将皮质结合的变化转换为相对于wt小鼠的Z评分，将相对于淀粉样变性的小胶质细胞活化定义为Z评分差异（TSPO-Aβ）。使用活化小胶质细胞（Iba-1）的3D免疫组织化学和胶质Aβ（甲氧基-X 04）的组织学，我们测量了相对于斑块大小和斑块边缘距离的小胶质细胞脑分数。在APP-SL 70小鼠中，Aβ-PET结合率随年龄呈指数增长，而TSPO结合率呈倒U形增长。纵向Z评分差异随年龄增长而下降，表明小胶质细胞反应相对于老年APP-SL 70小鼠中淀粉样变性的增加而下降。小胶质细胞脑体积分数与邻近斑块大小呈负相关，而与Aβ斑块的接近程度随年龄增加而增加。在APP-SL 70小鼠中，随着年龄的增长，小胶质细胞活性相对于正在进行的淀粉样变性而降低。斑块相关的小胶质细胞脑分数饱和，并与斑块大小随年龄增长呈负相关。
Causal associations between microglia activation and β-amyloid (Aβ) accumulation during the progression of Alzheimer’s disease (AD) remain a matter of controversy. Therefore, we used longitudinal dual tracer in vivo small animal positron emission tomography (μPET) imaging to resolve the progression of the association between Aβ deposition and microglial responses during aging of an Aβ mouse model. APP-SL70 mice (N = 17; baseline age 3.2–8.5 months) and age-matched C57Bl/6 controls (wildtype (wt)) were investigated longitudinally for 6 months using Aβ (18F-florbetaben) and 18 kDa translocator protein (TSPO) μPET (18F-GE180). Changes in cortical binding were transformed to Z-scores relative to wt mice, and microglial activation relative to amyloidosis was defined as the Z-score difference (TSPO—Aβ). Using 3D immunohistochemistry for activated microglia (Iba-1) and histology for fibrillary Aβ (methoxy-X04), we measure microglial brain fraction relative to plaque size and the distance from plaque margins. Aβ-PET binding increased exponentially as a function of age in APP-SL70 mice, whereas TSPO binding had an inverse U-shape growth function. Longitudinal Z-score differences declined with aging, suggesting that microglial response declined relative to increasing amyloidosis in aging APP-SL70 mice. Microglial brain volume fraction was inversely related to adjacent plaque size, while the proximity to Aβ plaques increased with age. Microglial activity decreases relative to ongoing amyloidosis with aging in APP-SL70 mice. The plaque-associated microglial brain fraction saturated and correlated negatively with increasing plaque size with aging.
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影响因子：
5.3
作者：
Hickman, Suzanne E.;Allison, Elizabeth K.;El Khoury, Joseph
通讯作者：
El Khoury, Joseph
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Fernández-Arjona MDM;Grondona JM;Granados-Durán P;Fernández-Llebrez P;López-Ávalos MD
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Helmchen, F
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