Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism
Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism
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DOI：
10.15252/emmm.201809711
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发表时间：
2019-06-01
影响因子：
11.1
通讯作者：
Haass, Christian
中科院分区：
文献类型：
--
作者：
Goetzl, Julia K.;Brendel, Matthias;Haass, Christian
小胶质细胞采用多种命运，其中稳态小胶质细胞（HM）和小胶质细胞神经退行性表型（MGnD）代表两个相反的末端。在小胶质细胞中选择性表达的基因中的许多变体与神经退行性疾病如阿尔茨海默病（AD）和额颞叶变性（FTLD）的风险增加相关。这些基因包括颗粒蛋白前体（GRN）和髓样细胞上表达的触发受体2（TREM 2）。两者都通过涉及功能丧失的机制引起神经变性。我们现在已经从Grn（-/-）小鼠中分离出小胶质细胞，并将其转录组与Trem 2（-/-）小鼠的转录组进行了比较。令人惊讶的是，虽然Trem 2的缺失增强了与稳态相关的基因的表达，但来自Grn（-/-）小鼠的小胶质细胞显示出MGnD分子特征的相互激活和HM基因特征的抑制。相反的mRNA表达谱与不同的功能表型相关。尽管TREM 2和颗粒蛋白前体的缺失导致小胶质细胞相反的激活状态和功能表型，但脑的FDG（氟-2-脱氧-d-葡萄糖）-mu PET显示在两种情况下葡萄糖代谢降低，表明相反的小胶质细胞表型导致类似的广泛脑功能障碍。
Microglia adopt numerous fates with homeostatic microglia (HM) and a microglial neurodegenerative phenotype (MGnD) representing two opposite ends. A number of variants in genes selectively expressed in microglia are associated with an increased risk for neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). Among these genes are progranulin (GRN) and the triggering receptor expressed on myeloid cells 2 (TREM2). Both cause neurodegeneration by mechanisms involving loss of function. We have now isolated microglia from Grn(-/-) mice and compared their transcriptomes to those of Trem2(-/-) mice. Surprisingly, while loss of Trem2 enhances the expression of genes associated with a homeostatic state, microglia derived from Grn(-/-) mice showed a reciprocal activation of the MGnD molecular signature and suppression of gene characteristic for HM. The opposite mRNA expression profiles are associated with divergent functional phenotypes. Although loss of TREM2 and progranulin resulted in opposite activation states and functional phenotypes of microglia, FDG (fluoro-2-deoxy-d-glucose)-mu PET of brain revealed reduced glucose metabolism in both conditions, suggesting that opposite microglial phenotypes result in similar wide spread brain dysfunction.