Glial activation is moderated by sex in response to amyloidosis but not to tau pathology in mouse models of neurodegenerative diseases.
Glial activation is moderated by sex in response to amyloidosis but not to tau pathology in mouse models of neurodegenerative diseases.
复制标题
DOI：
10.1186/s12974-020-02046-2
复制
发表时间：
2020-12-14
影响因子：
9.3
通讯作者：
Brendel M
中科院分区：
文献类型：
--
作者：
Biechele G;Franzmeier N;Blume T;Ewers M;Luque JM;Eckenweber F;Sacher C;Beyer L;Ruch-Rubinstein F;Lindner S;Gildehaus FJ;von Ungern-Sternberg B;Cumming P;Bartenstein P;Rominger A;Höglinger GU;Herms J;Brendel M
通过18-kDa转运蛋白正电子发射断层扫描（TSPO-PET）配体对神经炎症的体内评估在神经退行性疾病的临床前和临床研究中受到越来越多的关注。对于认知正常的人类，已经报道了更高的TSPO-PET结合作为女性中小胶质细胞活化的替代物，但是尚未在神经变性的啮齿动物模型及其对照中评价这种作用。因此，我们的目的是研究性别对淀粉样蛋白和tau蛋白小鼠模型和野生型对照中小胶质细胞活化的影响。在2至12月龄之间纵向评估C57 B1/6（野生型）、AppNL-G-F（β-淀粉样蛋白模型）和P301 S（tau模型）小鼠的TSPO-PET（18F-GE-180）数据。AppNL-G-F组还接受了纵向β-淀粉样蛋白-PET成像（Aβ-PET; 18 F-florbetaben）。PET结果通过小胶质细胞（Iba-1，CD 68），星形胶质细胞（GFAP）和tau（AT 8）标记物的免疫组织化学研究得到证实和验证。使用PET数据的线性混合模型和免疫组织化学的方差分析，按性别比较大脑皮层的结果。野生型小鼠显示TSPO-PET信号随时间增加（雌性+23%，雄性+4%），具有显著的性别×年龄相互作用（T =-4.171，p < 0.001）。Aβ模型AppNL-G-F小鼠还显示出显著的性别×年龄相互作用（T = − 2.953，p = 0.0048），其中雌性AppNL-G-F小鼠的皮质TSPO-PET值增加了31%，而雄性小鼠组从2.5至10月龄仅增加了6%。小胶质细胞标志物Iba-1和CD 68的免疫组织化学证实了10个月大雄性和雌性小鼠的TSPO-PET结果。相同AppNL-G-F小鼠的Aβ-PET显示无显著的性别×年龄相互作用（T = 0.425，p = 0.673）。P301 S tau模型显示，从2月龄到8.5月龄，TSPO-PET的皮质显著增加（女性+32%，男性+36%），没有任何显著的性别×年龄相互作用（T =-0.671，p = 0.504），Iba-1、CD 68或AT 8免疫组织化学无性别差异。雌性小鼠在衰老和响应淀粉样变性中显示性别依赖性小胶质细胞活化，但不响应tau病理学。这要求在神经变性小鼠模型中的小胶质细胞活化的TSPO-PET研究中以及通过扩展在人类研究中考虑性别差异。
In vivo assessment of neuroinflammation by 18-kDa translocator protein positron-emission-tomography (TSPO-PET) ligands receives growing interest in preclinical and clinical research of neurodegenerative disorders. Higher TSPO-PET binding as a surrogate for microglial activation in females has been reported for cognitively normal humans, but such effects have not yet been evaluated in rodent models of neurodegeneration and their controls. Thus, we aimed to investigate the impact of sex on microglial activation in amyloid and tau mouse models and wild-type controls. TSPO-PET (18F-GE-180) data of C57Bl/6 (wild-type), AppNL-G-F (β-amyloid model), and P301S (tau model) mice was assessed longitudinally between 2 and 12 months of age. The AppNL-G-F group also underwent longitudinal β-amyloid-PET imaging (Aβ-PET; 18F-florbetaben). PET results were confirmed and validated by immunohistochemical investigation of microglial (Iba-1, CD68), astrocytic (GFAP), and tau (AT8) markers. Findings in cerebral cortex were compared by sex using linear mixed models for PET data and analysis of variance for immunohistochemistry. Wild-type mice showed an increased TSPO-PET signal over time (female +23%, male +4%), with a significant sex × age interaction (T = − 4.171, p < 0.001). The Aβ model AppNL-G-F mice also showed a significant sex × age interaction (T = − 2.953, p = 0.0048), where cortical TSPO-PET values increased by 31% in female AppNL-G-F mice, versus only 6% in the male mice group from 2.5 to 10 months of age. Immunohistochemistry for the microglial markers Iba-1 and CD68 confirmed the TSPO-PET findings in male and female mice aged 10 months. Aβ-PET in the same AppNL-G-F mice indicated no significant sex × age interaction (T = 0.425, p = 0.673). The P301S tau model showed strong cortical increases of TSPO-PET from 2 to 8.5 months of age (female + 32%, male + 36%), without any significant sex × age interaction (T = − 0.671, p = 0.504), and no sex differences in Iba-1, CD68, or AT8 immunohistochemistry. Female mice indicate sex-dependent microglia activation in aging and in response to amyloidosis but not in response to tau pathology. This calls for consideration of sex difference in TSPO-PET studies of microglial activation in mouse models of neurodegeneration and by extension in human studies.
登录
查看更多内容
影响因子：
25
作者：
Parhizkar, Samira;Arzberger, Thomas;Haass, Christian
通讯作者：
Haass, Christian
影响因子：
9.3
作者：
Brendel, Matthias;Focke, Carola;Rominger, Axel
通讯作者：
Rominger, Axel
影响因子：
9.3
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
通讯作者：
Brendel M
DOI：
10.1016/j.jalz.2011.10.007
发表时间：
2012-01
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Hyman BT;Phelps CH;Beach TG;Bigio EH;Cairns NJ;Carrillo MC;Dickson DW;Duyckaerts C;Frosch MP;Masliah E;Mirra SS;Nelson PT;Schneider JA;Thal DR;Thies B;Trojanowski JQ;Vinters HV;Montine TJ
通讯作者：
Montine TJ
影响因子：
9.3
作者：
Brendel, Matthias;Probst, Federico;Rominger, Axel
通讯作者：
Rominger, Axel