Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system: new aspects on Alzheimer's disease
Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system: new aspects on Alzheimer's disease
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DOI：
10.1007/s00401-015-1394-3
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发表时间：
2015-04-01
影响因子：
12.7
通讯作者：
Hokfelt, Tomas
中科院分区：
文献类型：
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作者：
Adori, Csaba;Glueck, Laura;Hokfelt, Tomas
阿尔茨海默病和其他年龄相关的神经退行性疾病与去甲肾上腺素能蓝斑（LC）的恶化有关，这可能是情绪和记忆功能障碍的触发因素。LC去甲肾上腺素能神经元表现出特别高水平的生长抑素结合位点。这是值得注意的，因为皮质和下丘脑生长抑素含量在神经退行性病变中减少。然而，生长抑素信号缺陷在维持去甲肾上腺素能投射中的可能作用仍然未知。在这里，我们部署了组织微阵列，免疫组织化学，定量形态测定和mRNA分析在一个队列的阿尔茨海默氏症和年龄匹配的对照组的大脑结合生长抑素受体缺乏症的遗传模型，以建立之间的因果关系，停用生长抑素信号和去甲肾上腺素能神经变性。在阿尔茨海默氏病，我们发现显着减少生长抑素蛋白的表达在颞叶皮质，异常聚类和隆起的酪氨酸羟化酶免疫反应传入。因此，生长抑素受体2（SSTR 2）mRNA在人LC中高度表达，其水平从Braak III/IV期及以后显著降低，即，这是老年痴呆症晚期之前的一个过程LC神经元中SSTR 2转录物的损失似乎是选择性的，因为酪氨酸羟化酶、多巴胺β-羟化酶、甘丙肽或甘丙肽受体3 mRNA保持不变。我们在Sstr 2（-/-）小鼠中模拟了这些致病性变化，与Sstr 1（-/-）或Sstr 4（-/-）基因型不同，它们显示出中枢去甲肾上腺素能投射的选择性、全局性和进行性变性。然而，在Sstr 2（-/-）小鼠中，LC中的神经元胞体被发现是完整的，直到成年后期（< 8个月）。相反，上级颈神经节中的去甲肾上腺素能神经元缺乏SSTR 2，并且正如预期的那样，头部区域的交感神经支配没有显示出任何退化迹象。我们的研究结果表明，SSTR 2介导的信号是不可或缺的中央去甲肾上腺素能预测在系统水平的维护，和生长抑素受体2功能的早期损失可能与阿尔茨海默病的去甲肾上腺素能系统的选择性脆弱性。
Alzheimer's disease and other age-related neurodegenerative disorders are associated with deterioration of the noradrenergic locus coeruleus (LC), a probable trigger for mood and memory dysfunction. LC noradrenergic neurons exhibit particularly high levels of somatostatin binding sites. This is noteworthy since cortical and hypothalamic somatostatin content is reduced in neurodegenerative pathologies. Yet a possible role of a somatostatin signal deficit in the maintenance of noradrenergic projections remains unknown. Here, we deployed tissue microarrays, immunohistochemistry, quantitative morphometry and mRNA profiling in a cohort of Alzheimer's and age-matched control brains in combination with genetic models of somatostatin receptor deficiency to establish causality between defunct somatostatin signalling and noradrenergic neurodegeneration. In Alzheimer's disease, we found significantly reduced somatostatin protein expression in the temporal cortex, with aberrant clustering and bulging of tyrosine hydroxylase-immunoreactive afferents. As such, somatostatin receptor 2 (SSTR2) mRNA was highly expressed in the human LC, with its levels significantly decreasing from Braak stages III/IV and onwards, i.e., a process preceding advanced Alzheimer's pathology. The loss of SSTR2 transcripts in the LC neurons appeared selective, since tyrosine hydroxylase, dopamine beta-hydroxylase, galanin or galanin receptor 3 mRNAs remained unchanged. We modeled these pathogenic changes in Sstr2 (-/-) mice and, unlike in Sstr1 (-/-) or Sstr4 (-/-) genotypes, they showed selective, global and progressive degeneration of their central noradrenergic projections. However, neuronal perikarya in the LC were found intact until late adulthood (< 8 months) in Sstr2 (-/-) mice. In contrast, the noradrenergic neurons in the superior cervical ganglion lacked SSTR2 and, as expected, the sympathetic innervation of the head region did not show any signs of degeneration. Our results indicate that SSTR2-mediated signaling is integral to the maintenance of central noradrenergic projections at the system level, and that early loss of somatostatin receptor 2 function may be associated with the selective vulnerability of the noradrenergic system in Alzheimer's disease.