Gnörich Johannes, Reifschneider Anika, Wind Karin, Zatcepin Artem, Kunte Sebastian T, Beumers Philipp, Bartos Laura M, Wiedemann Thomas, Grosch Maximilian, Xiang Xianyuan, Fard Maryam K, Ruch Francois, Werner Georg, Koehler Mara, Slemann Luna, Hummel Selina, Briel Nils, Blume Tanja, Shi Yuan, Biechele Gloria, Beyer Leonie, Eckenweber Florian, Scheifele Maximilian, Bartenstein Peter, Albert Nathalie L, Herms Jochen, Tahirovic Sabina, Haass Christian, Capell Anja, Ziegler Sibylle, Brendel Matthias
Department of Nuclear Medicine, University Hospital, Ludwig-Maximilians-Universität München, Marchioninistrasse 15, 81377, Munich, Germany.
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
J Neuroinflammation. 2023 Feb 24;20(1):47. doi: 10.1186/s12974-023-02735-8.
We aimed to investigate the impact of microglial activity and microglial FDG uptake on metabolic connectivity, since microglial activation states determine FDG-PET alterations. Metabolic connectivity refers to a concept of interacting metabolic brain regions and receives growing interest in approaching complex cerebral metabolic networks in neurodegenerative diseases. However, underlying sources of metabolic connectivity remain to be elucidated.
We analyzed metabolic networks measured by interregional correlation coefficients (ICCs) of FDG-PET scans in WT mice and in mice with mutations in progranulin (Grn) or triggering receptor expressed on myeloid cells 2 (Trem2) knockouts () as well as in double mutant Grn/Trem2 mice. We selected those rodent models as they represent opposite microglial signatures with disease associated microglia in Grn mice and microglia locked in a homeostatic state in Trem2 mice; however, both resulting in lower glucose uptake of the brain. The direct influence of microglia on metabolic networks was further determined by microglia depletion using a CSF1R inhibitor in WT mice at two different ages. Within maps of global mean scaled regional FDG uptake, 24 pre-established volumes of interest were applied and assigned to either cortical or subcortical networks. ICCs of all region pairs were calculated and z-transformed prior to group comparisons. FDG uptake of neurons, microglia, and astrocytes was determined in Grn and WT mice via assessment of single cell tracer uptake (scRadiotracing).
Microglia depletion by CSF1R inhibition resulted in a strong decrease of metabolic connectivity defined by decrease of mean cortical ICCs in WT mice at both ages studied (6-7 m; p = 0.0148, 9-10 m; p = 0.0191), when compared to vehicle-treated age-matched WT mice. Grn, Trem2 and Grn/Trem2 mice all displayed reduced FDG-PET signals when compared to WT mice. However, when analyzing metabolic networks, a distinct increase of ICCs was observed in Grn mice when compared to WT mice in cortical (p < 0.0001) and hippocampal (p < 0.0001) networks. In contrast, Trem2 mice did not show significant alterations in metabolic connectivity when compared to WT. Furthermore, the increased metabolic connectivity in Grn mice was completely suppressed in Grn/Trem2 mice. Grn mice exhibited a severe loss of neuronal FDG uptake (- 61%, p < 0.0001) which shifted allocation of cellular brain FDG uptake to microglia (42% in Grn vs. 22% in WT).
Presence, absence, and activation of microglia have a strong impact on metabolic connectivity of the mouse brain. Enhanced metabolic connectivity is associated with increased microglial FDG allocation.
由于小胶质细胞激活状态决定了氟代脱氧葡萄糖正电子发射断层扫描（FDG-PET）的改变，我们旨在研究小胶质细胞活性和小胶质细胞FDG摄取对代谢连通性的影响。代谢连通性是指相互作用的脑代谢区域的概念，在研究神经退行性疾病中的复杂脑代谢网络时受到越来越多的关注。然而，代谢连通性的潜在来源仍有待阐明。
我们分析了野生型（WT）小鼠、颗粒蛋白前体（Grn）突变小鼠、髓系细胞触发受体2（Trem2）基因敲除小鼠以及双突变Grn/Trem2小鼠的FDG-PET扫描的区域间相关系数（ICC）所测量的代谢网络。我们选择这些啮齿动物模型是因为它们代表了相反的小胶质细胞特征，Grn小鼠中存在与疾病相关的小胶质细胞，而Trem2小鼠中的小胶质细胞处于稳态；然而，两者都会导致脑葡萄糖摄取降低。通过在两个不同年龄的WT小鼠中使用集落刺激因子1受体（CSF1R）抑制剂清除小胶质细胞，进一步确定小胶质细胞对代谢网络的直接影响。在全球平均缩放区域FDG摄取图中，应用24个预先确定的感兴趣体积，并将其分配到皮质或皮质下网络。在进行组间比较之前，计算所有区域对的ICC并进行z变换。通过评估单细胞示踪剂摄取（单细胞放射性示踪）来确定Grn和WT小鼠中神经元、小胶质细胞和星形胶质细胞的FDG摄取。
与用载体处理的年龄匹配的WT小鼠相比，通过CSF1R抑制清除小胶质细胞导致在所研究的两个年龄的WT小鼠中，由平均皮质ICC降低所定义的代谢连通性显著降低（6 - 7月龄；p = 0.0148，9 - 10月龄；p = 0.0191）。与WT小鼠相比，Grn、Trem2和Grn/Trem2小鼠均显示FDG-PET信号降低。然而，在分析代谢网络时，与WT小鼠相比，Grn小鼠在皮质（p < 0.0001）和海马（p < 0.0001）网络中的ICC明显增加。相比之下，与WT小鼠相比，Trem2小鼠在代谢连通性方面未显示出显著变化。此外，Grn/Trem2小鼠完全抑制了Grn小鼠中增加的代谢连通性。Grn小鼠表现出神经元FDG摄取严重丧失（-61%，p < 0.0001），这将细胞脑FDG摄取的分配转移到小胶质细胞（Grn小鼠中为42%，而WT小鼠中为22%）。
小胶质细胞的存在、缺失和激活对小鼠脑的代谢连通性有强烈影响。增强的代谢连通性与增加的小胶质细胞FDG分配相关。
