Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Marchioninstraße 15, 81377, Munich, Germany.
Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, Munich, Germany.
J Neuroinflammation. 2020 Dec 14;17(1):374. doi: 10.1186/s12974-020-02046-2.
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 (F-GE-180) data of C57Bl/6 (wild-type), App (β-amyloid model), and P301S (tau model) mice was assessed longitudinally between 2 and 12 months of age. The App group also underwent longitudinal β-amyloid-PET imaging (Aβ-PET; F-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 App mice also showed a significant sex × age interaction (T = - 2.953, p = 0.0048), where cortical TSPO-PET values increased by 31% in female App 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 App 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.
在神经退行性疾病的临床前和临床研究中，18 kDa 转位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受到越来越多的关注。已有报道称，在认知正常的人类中，女性的 TSPO-PET 结合更高，可作为小胶质细胞激活的替代物，但这种影响尚未在神经退行性变的啮齿动物模型及其对照中得到评估。因此，我们旨在研究性别对淀粉样蛋白和 tau 小鼠模型以及野生型对照中小胶质细胞激活的影响。
在 2 至 12 个月大期间，对 C57Bl/6（野生型）、App（β-淀粉样蛋白模型）和 P301S（tau 模型）小鼠进行 TSPO-PET（F-GE-180）数据的纵向评估。App 组还进行了β-淀粉样蛋白-PET（Aβ-PET；F-氟比洛芬）的纵向成像。通过对小胶质细胞（Iba-1、CD68）、星形胶质细胞（GFAP）和 tau（AT8）标志物的免疫组织化学研究，对 PET 结果进行了确认和验证。使用 PET 数据的线性混合模型和免疫组织化学的方差分析，根据性别比较大脑皮层的结果。
野生型小鼠的 TSPO-PET 信号随时间呈上升趋势（女性增加 23%，男性增加 4%），具有显著的性别×年龄交互作用（T=-4.171，p<0.001）。Aβ 模型 App 小鼠也显示出显著的性别×年龄交互作用（T=-2.953，p=0.0048），在 2.5 至 10 个月时，皮质 TSPO-PET 值在雌性 App 小鼠中增加了 31%，而雄性小鼠组中仅增加了 6%。10 个月大的雄性和雌性小鼠的小胶质细胞标志物 Iba-1 和 CD68 的免疫组织化学证实了 TSPO-PET 的发现。同一 App 小鼠的 Aβ-PET 显示无显著性别×年龄交互作用（T=0.425，p=0.673）。P301S tau 模型从 2 至 8.5 个月大时皮质 TSPO-PET 呈强烈增加（女性增加 32%，男性增加 36%），无显著性别×年龄交互作用（T=-0.671，p=0.504），且 Iba-1、CD68 或 AT8 免疫组织化学无性别差异。
雌性小鼠在衰老和淀粉样变性时表现出依赖于性别的小胶质细胞激活，但在 tau 病理时没有。这呼吁在神经退行性变的小鼠模型和人类研究中，考虑 TSPO-PET 研究中小胶质细胞激活的性别差异。
