We present in vitro and in vivo evidence demonstrating that Amyloid Precursor Protein (APP) acts as an essential instigator of reactive astrogliosis. Cell-specific overexpression of APP in cultured astrocytes led to remodelling of the intermediate filament network, enhancement of cytokine production and activation of cellular programs centred around the interferon (IFN) pathway, all signs of reactive astrogliosis. Conversely, APP deletion in cultured astrocytes abrogated remodelling of the intermediate filament network and blunted expression of IFN stimulated gene (ISG) products in response to lipopolysaccharide (LPS). 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 (GFAP) observed canonically in astrocytes in response to TBI. Thus, APP represents a molecular inducer and regulator of 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 San Diego USA

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 CA 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

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

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

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

PsychoGenics Paramus 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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Acta Physiol (Oxf). 2024 Jun;240(6):e14142. doi: 10.1111/apha.14142. PubMed

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