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IGF-1 Gene Transfer Modifies Inflammatory Environment and Gene Expression in the Caudate-Putamen of Aged Female Rat Brain

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Abstract

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 Iba1+Arg1+ 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.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

Arg1:

Arginase 1

CNS:

Central nervous system

CPu:

Caudate-putamen unit

DA:

Dopamine

DEGs:

Differentially expressed genes

DsRed:

Red fluorescent protein from Discosoma sp.

Iba1:

Ionized calcium-binding adapter molecule 1

IGF-1:

Insulin-like growth factor-1

ICV:

Intracerebroventricular

MB:

Marble burying

OF:

Open field

RAd:

Recombinant adenoviral vector

TH:

Tyrosine hydroxylase

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Acknowledgements

We thank Natalia Scelsio, Jana Weiβ-Müller, and Robin Piecha for technical assistance, to Araceli Bigres for animal management, as well as to Dr. Andrea Pereyra for English revision assistance. We acknowledge IBRO and Boehringer Ingelheim Fonds support on EF-L’s short stays in Germany.

Funding

This study was supported by grants from the Argentine Agency for the Promotion of Science and Technology (grant number #PICT13-1119) and the Argentine Research Council (CONICET) (grant number PIP0618) to MJB, grants from the Universidad Nacional de La Plata (grant number M184 to CH and V270 to EP) and grant from the Deutsche Forschungsgemeinschaft (DFG) (grant number SP 1555/2–1) to BS.

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Author notes

  1. María José Bellini and Claudia Beatriz Hereñú contributed equally to this work.

Authors and Affiliations

  1. 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

    Eugenia Falomir-Lockhart, Franco Juan Cruz Dolcetti, Jerónimo Pennini, María Florencia Zappa Villar & María José Bellini

  2. Instituto de Farmacología Experimental de Córdoba-CONICET, Departamento de Farmacología, Facultad de Ciencias Químicas, UNC-CONICET, CP500, Córdoba, Argentina

    Macarena Lorena Herrera & Claudia Beatriz Hereñú

  3. NGS- Integrative Genomics Core Unit (NIG), Institute of Human Genetics, University Medical Center Göttingen (UMG), Göttingen, Germany

    Gabriela Salinas

  4. Laboratorio de Análisis de Imágenes (LAI), Facultad de Ciencias Veterinarias, UNLP, La Plata, Argentina

    Enrique Portiansky

  5. Institute of Anatomy, University of Rostock, Rostock, Germany

    Björn Spittau

  6. Anatomy and Cell Biology, Medical School OWL, Bielefeld University, Bielefeld, Germany

    Björn Spittau

  7. Centro de Investigaciones Inmunológicas Básicas Y Aplicadas (CINIBA), Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, CP1900, Argentina

    Ezequiel Lacunza

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Contributions

EF-L, CH, and MJB designed the experiments. EF-L, FJCD, JP, and MFVZ performed the experiments. GS performed the RNAseq. EL performed the analysis of the RNAseq. EF-L, FJCD, MLH, EP, EL, and MJB analyzed the data. EF-L, MLH, EL, BS, EP, and MJB wrote the manuscript. All authors have commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Claudia Beatriz Hereñú or María José Bellini.

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All experiments with animals have been approved by our institutional Committee for the Care and Use of Laboratory Animals (Protocol #T09-01–2013).

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Falomir-Lockhart, E., Dolcetti, F.J.C., Herrera, M.L. et al. IGF-1 Gene Transfer Modifies Inflammatory Environment and Gene Expression in the Caudate-Putamen of Aged Female Rat Brain. Mol Neurobiol 59, 3337–3352 (2022). https://doi.org/10.1007/s12035-022-02791-w

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