Laboratorio de Bioquímica del Envejecimiento, Instituto de Investigaciones Bioquímicas de La Plata (INIBIOLP), Facultad de Ciencias Médicas, UNLP-CONICET, Av. 60 s/n., La Plata, CP1900, Buenos Aires, Argentina.
Instituto de Farmacología Experimental de Córdoba-CONICET, Departamento de Farmacología, Facultad de Ciencias Químicas, UNC-CONICET, CP500, Córdoba, Argentina.
Mol Neurobiol. 2022 Jun;59(6):3337-3352. doi: 10.1007/s12035-022-02791-w. Epub 2022 Mar 19.
Brain aging is characterized by chronic neuroinflammation caused by activation of glial cells, mainly microglia, leading to alterations in homeostasis of the central nervous system. Microglial cells are constantly surveying their environment to detect and respond to diverse signals. During aging, microglia undergoes a process of senescence, characterized by loss of ramifications, spheroid formation, and fragmented processes, among other abnormalities. Therefore, the study of changes in microglia during is of great relevance to understand age-related declines in cognitive and motor function. We have targeted the deleterious effects of aging by implementing IGF-1 gene transfer, employing recombinant adenoviral vectors (RAds) as a delivery system. In this study, we performed intracerebroventricular (ICV) RAd-IGF-1 or control injection on aged female rats and evaluated its effect on caudate-putamen unit (CPu) gene expression and inflammatory state. Our results demonstrate that IGF-1 overexpression modified aged microglia of the CPu towards an anti-inflammatory condition increasing the proportion of double immuno-positive Iba1Arg1 cells. We also observed that phosphorylation of Akt was increased in animals treated with RAd-IGF-1. Moreover, IGF-1 gene transfer was able to regulate CPu pro-inflammatory environment in female aged rats by down-regulating the expression of genes typically overexpressed during aging. RNA-Seq data analysis identified 97 down-modulated DEG in the IGF-1 group as compared to the DsRed one. Interestingly, 12 of these DEG are commonly overexpressed during aging, and 9 out of 12 are expressed in microglia/macrophages and are involved in different processes that lead to neuroinflammation and/or neuronal loss. Finally, we observed that IGF-1 overexpression led to an improvement in motor functions. Although further studies are necessary, with the present results, we conclude that IGF-1 gene transfer is modifying both the pro-inflammatory environment and activation of microglia/macrophages in CPu. In this regard, IGF-1 gene transfer could counteract the neuroinflammatory effects associated with aging and improve motor functions in senile animals.
大脑老化的特征是胶质细胞（主要是小胶质细胞）的慢性神经炎症激活，导致中枢神经系统的内稳态发生改变。小胶质细胞不断地监测其环境，以检测和响应各种信号。在衰老过程中，小胶质细胞经历衰老过程，表现为分支丧失、球体形成和碎片化过程等异常。因此，研究小胶质细胞在老化过程中的变化对于理解与年龄相关的认知和运动功能下降非常重要。我们通过实施 IGF-1 基因转移来靶向衰老的有害影响，使用重组腺病毒载体（RAds）作为递送系统。在这项研究中，我们对老年雌性大鼠进行了侧脑室（ICV）RAd-IGF-1 或对照注射，并评估了其对尾壳核单位（CPu）基因表达和炎症状态的影响。我们的结果表明，IGF-1 的过表达使 CPu 中的衰老小胶质细胞向抗炎状态转变，增加了 Iba1Arg1 双免疫阳性细胞的比例。我们还观察到，用 RAd-IGF-1 处理的动物中 Akt 的磷酸化增加。此外，IGF-1 基因转移能够通过下调通常在衰老过程中过度表达的基因来调节老年雌性大鼠 CPu 的促炎环境。RNA-Seq 数据分析确定了 IGF-1 组与 DsRed 组相比有 97 个下调的差异表达基因（DEG）。有趣的是，这 97 个 DEG 中有 12 个在衰老过程中过度表达，其中 12 个中有 9 个在小胶质细胞/巨噬细胞中表达，并参与导致神经炎症和/或神经元丢失的不同过程。最后，我们观察到 IGF-1 的过表达导致运动功能的改善。尽管还需要进一步的研究，但根据目前的结果，我们得出结论，IGF-1 基因转移既改变了 CPu 中的促炎环境，又改变了小胶质细胞/巨噬细胞的激活。在这方面，IGF-1 基因转移可以对抗与衰老相关的神经炎症效应，并改善老年动物的运动功能。
