Amyloid precursor protein induces reactive astrogliosis

Gretsen Velezmoro Jauregui, Dragana Vukić, Isaac G Onyango, Carlos Arias, Jan S Novotný, Kateřina Texlová, Shanshan Wang, Kristina Locker Kovačovicova, Natalie Polakova, Jana Zelinkova, Maria Čarna, Valentina Lacovich, Brian P Head, Daniel Havas, Martin Mistrik, Robert Zorec, Alexei Verkhratsky, Liam Keegan, Mary A O'Connell, Robert RissmanGorazd B Stokin

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)e14142
JournalActa physiologica (Oxford, England)
Volume240
Issue number6
DOIs
Publication statusPublished - 1 Jun 2024

Keywords

  • Animals
  • Gliosis/metabolism
  • Amyloid beta-Protein Precursor/metabolism
  • Astrocytes/metabolism
  • Mice
  • Cells, Cultured
  • Mice, Inbred C57BL
  • Brain Injuries, Traumatic/metabolism
  • Mice, Knockout

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