Department of Biochemistry and Immunology, Institute of Biological Sciences (ICB), Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil.
Department of Morphology, Institute of Biological Sciences (ICB), Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil.
Neurochem Int. 2019 Jun;126:218-228. doi: 10.1016/j.neuint.2019.03.020. Epub 2019 Mar 29.
The growing elderly population world widely prompts the need for studies regarding aged brain and its susceptibility to neurodegenerative diseases. It has been shown that aged brain exhibits several alterations, including neuroinflammation, which prone this organ to neurodegenerative processes. Metabotropic glutamate receptor 5 (mGlu receptor) has a role in neuronal cell loss and inflammation. Although the relevance of mGlu receptor in different diseases has been investigated, its involvement in normal brain aging remains unclear. In the present study, we used the mGlu receptor knockout (mGluR5) mice, a model of Huntington's Disease (BACHD), and the double mutant mice (mGluR5/BACHD), at the ages of 2, 6 and 12 months, to investigate whether mGlu receptor has a role in brain aging. We demonstrated that mGluR5 mice exhibit diminished number of neurons at 12 months of age in the cortex and striatum, similarly to what was observed in the case of BACHD and mGluR5/BACHD mice. In addition, ablation of mGlu receptor increased the number of astrocytes and microglia in BACHD and wild type (WT) mice in an age-dependent manner in the cortical region, but not in the striatum. Interestingly, 12-month-old mGluR5 mice induced microglia activation, evidenced by increased CD68 expression and diminished number of microglia ramifications in skeleton analyses. Importantly, the presence of mutant huntingtin and the absence of mGlu receptor promoted decreased levels of fractalkine expression in aged mice, which could account for the decreased levels of microglia activation in these mice. Together, our data provide evidence that mGlu receptor plays a role in brain aging by modulating different cell types in the central nervous system (CNS).
全球老年人口的增长促使人们需要研究老年大脑及其对神经退行性疾病的易感性。研究表明，老年大脑表现出多种改变，包括神经炎症，这使得该器官容易发生神经退行性过程。代谢型谷氨酸受体 5 (mGlu 受体) 在神经元细胞丢失和炎症中起作用。尽管已经研究了 mGlu 受体在不同疾病中的相关性，但它在正常大脑衰老中的作用仍不清楚。在本研究中，我们使用了 mGlu 受体敲除 (mGluR5) 小鼠、亨廷顿病 (BACHD) 模型和双突变小鼠 (mGluR5/BACHD)，在 2、6 和 12 个月大时，研究 mGlu 受体是否在大脑衰老中起作用。我们证明，mGluR5 小鼠在 12 个月大时，皮质和纹状体中的神经元数量减少，这与 BACHD 和 mGluR5/BACHD 小鼠的情况相似。此外，mGlu 受体的缺失会以年龄依赖的方式增加 BACHD 和野生型 (WT) 小鼠皮质区域中星形胶质细胞和小胶质细胞的数量，但在纹状体中则不会。有趣的是，12 个月大的 mGluR5 小鼠诱导小胶质细胞激活，证据是 CD68 表达增加和骨架分析中小胶质细胞分支数量减少。重要的是，突变型亨廷顿蛋白的存在和 mGlu 受体的缺失促进了老年小鼠中 fractalkine 表达水平的降低，这可能是这些小鼠中小胶质细胞激活水平降低的原因。总之，我们的数据提供了证据，表明 mGlu 受体通过调节中枢神经系统 (CNS) 中的不同细胞类型在大脑衰老中起作用。
