AIM: Astrocytes respond to stressors by acquiring a reactive state characterized by changes in their morphology and function. Molecules underlying reactive astrogliosis, however, remain largely unknown. Given that several studies observed increase in the Amyloid Precursor Protein (APP) in reactive astrocytes, we here test whether APP plays a role in reactive astrogliosis. METHODS: We investigated whether APP instigates reactive astroglios by examining in vitro and in vivo the morphology and function of naive and APP-deficient astrocytes in response to APP and well-established stressors. RESULTS: Overexpression of APP in cultured astrocytes led to remodeling of the intermediate filament network, enhancement of cytokine production, and activation of cellular programs centered around the interferon (IFN) pathway, all signs of reactive astrogliosis. Conversely, APP deletion abrogated remodeling of the intermediate filament network and blunted expression of IFN-stimulated gene products in response to lipopolysaccharide. Following traumatic brain injury (TBI), mouse reactive astrocytes also exhibited an association between APP and IFN, while APP deletion curbed the increase in glial fibrillary acidic protein observed canonically in astrocytes in response to TBI. CONCLUSIONS: The APP thus represents a candidate molecular inducer and regulator of reactive astrogliosis. This finding has implications for understanding pathophysiology of neurodegenerative and other diseases of the nervous system characterized by reactive astrogliosis and opens potential new therapeutic avenues targeting APP and its pathways to modulate reactive astrogliosis.

Achucarro Centre for Neuroscience IIKERBASQUE Basque Foundation for Science Bilbao Spain

Celica Biomedical Technology Park Ljubljana Slovenia

Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Anesthesia University of California San Diego La Jolla California USA

Department of Biology Faculty of Medicine Masaryk University Brno Czech Republic

Department of Forensic Analytical Toxicology School of Forensic Medicine China Medical University Shenyang Liaoning Province China

Department of Neurology Gloucestershire Royal Hospital Gloucestershire NHS Foundation Trust Gloucester UK

Department of Neurosciences University of California San Diego La Jolla California USA

Department of Stem Cell Biology State Research Institute Centre for Innovative Medicine Vilnius Lithuania

Faculty of Biology Medicine and Health University of Manchester Manchester UK

Faculty of Medicine and Dentistry Institute of Molecular and Translational Medicine Palacky University Olomouc Olomouc Czech Republic

Faculty of Science National Centre for Biomedical Research Masaryk University Brno Czech Republic

Laboratory of Neuroendocrinology Molecular Cell Physiology Faculty of Medicine Institute of Pathophysiology University of Ljubljana Ljubljana Slovenia

PsychoGenics Paramus New Jersey USA

Translational Ageing and Neuroscience Program Centre for Translational Medicine International Clinical Research Centre St Anne's University Hospital Brno Czech Republic

Veterans Affairs San Diego Healthcare System San Diego USA

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bioRxiv. 2023 Dec 18:2023.12.18.571817. doi: 10.1101/2023.12.18.571817. PubMed

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