Abstract
Neurodegenerative diseases such as Alzheimer’s disease have been classically studied from a purely neuronocentric point of view. More recent evidences support the notion that other cell populations are involved in disease progression. In this sense, the possible pathogenic role of glial cells like astrocytes is increasingly being recognized. Once faced with tissue damage signals and other stimuli present in disease environments, astrocytes suffer many morphological and functional changes, a process referred as reactive astrogliosis. Studies from murine models and humans suggest that these complex and heterogeneous responses could manifest as disease-specific astrocyte phenotypes. Clear understanding of disease-associated astrocytes is a necessary step to fully disclose neurodegenerative processes, aiding in the design of new therapeutic and diagnostic strategies. In this work, we present the transcriptomics characterization of neurotoxic astrocytic cultures isolated from adult symptomatic animals of the triple transgenic mouse model of Alzheimer’s disease (3xTg-AD). According to the observed profile, 3xTg-AD neurotoxic astrocytes show various reactivity features including alteration of the extracellular matrix and release of pro-inflammatory and proliferative factors that could result in harmful effects to neurons. Moreover, these alterations could be a consequence of stress responses at the endoplasmic reticulum and mitochondria as well as of concomitant metabolic adaptations. Present results support the hypothesis that adaptive changes of astrocytic function induced by a stressed microenvironment could later promote harmful astrocyte phenotypes and further accelerate or induce neurodegenerative processes.
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Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
This work would not exist without the efforts of Dr. Pablo Díaz-Amarilla. Diego Carvalho specially thanks him for all the help received at the start of his thesis, as well as his honest pursuit of science. We thank Dr. Matthew Ryan Smith from Emory University for his aid in metabolic results interpretation. We would also like to thank all the team of CUDIM animal facility for their crucial work in animal care and assistance.
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This work was supported by Agencia Nacional de Investigación e Innovación (ANII) (grant numbers: POS_NAC_2017_1_140673, MOV_CA_2018_1_149736, PD_NAC_2018_1_149726), UK Embassy in Montevideo (grant number: UK_ID_2015-1–7), Programa de Desarrollo de las Ciencias Básicas (PEDECIBA), and Comisión Académica de Posgrado (CAP).
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D. C.: methodology, investigation, data curation, formal analysis, visualization, writing — original draft, writing — review and editing; P. D.-A.: conceptualization, methodology, investigation; R. D.: methodology, investigation, formal analysis, writing — review and editing; M. D. S.: investigation, writing — review and editing; P. D.: resources, final drafting collaboration; E. S.: resources, writing — review and editing; H. E.: conceptualization, writing — review and editing; J. A. A.-C.: conceptualization, writing — review and editing; F. A.: conceptualization, methodology, investigation, writing — original draft, writing — review and editing.
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Carvalho, D., Diaz-Amarilla, P., Dapueto, R. et al. Transcriptomic Analyses of Neurotoxic Astrocytes Derived from Adult Triple Transgenic Alzheimer’s Disease Mice. J Mol Neurosci 73, 487–515 (2023). https://doi.org/10.1007/s12031-023-02105-2
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DOI: https://doi.org/10.1007/s12031-023-02105-2