Astrocytes deliver CK1 to neurons via extracellular vesicles in response to inflammation promoting the translation and amyloidogenic processing of APP

Zhigang Li, Mohammed Moniruzzaman, Raha M. Dastgheyb, Seung Wan Yoo, Meina Wang, Hongbo Hao, Jia Liu, Patrizia Casaccia, Carlos Nogueras-Ortiz, Dimitrios Kapogiannis, Barbara S. Slusher, Norman J. Haughey

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30 Scopus citations

Abstract

Chronic inflammation is thought to contribute to the early pathogenesis of Alzheimer's disease (AD). However, the precise mechanism by which inflammatory cytokines promote the formation and deposition of Aβ remains unclear. Available data suggest that applications of inflammatory cytokines onto isolated neurons do not promote the formation of Aβ, suggesting an indirect mechanism of action. Based on evidence astrocyte derived extracellular vesicles (astrocyte derived EVs) regulate neuronal functions, and data that inflammatory cytokines can modify the molecular cargo of astrocyte derived EVs, we sought to determine if IL-1β promotes the formation of Aβ indirectly through actions of astrocyte derived EVs on neurons. The production of Aβ was increased when neurons were exposed to astrocyte derived EVs shed in response to IL-1β (astrocyte derived EV-IL-1β). The mechanism for this effect involved an enrichment of Casein kinase 1 (CK1) in astrocyte derived EV-IL-1β. This astrocyte derived CK1 was delivered to neurons where it formed a complex with neuronal APC and GSK3 to inhibit the β-catenin degradation. Stabilized β-catenin translocated to the nucleus and bound to Hnrnpc gene at promoter regions. An increased cellular concentration of hnRNP C promoted the translation of APP by outcompeting the translational repressor fragile X mental retardation protein (FMRP) bound to APP mRNA. An increased amount of APP protein became co-localized with BACE1 in enlarged membrane microdomains concurrent with increased production of Aβ. These findings identify a mechanism whereby inflammation promotes the formation of Aβ through the actions of astrocyte derived EV-IL-1β on neurons.

Original languageEnglish
Article numbere12035
JournalJournal of Extracellular Vesicles
Volume10
Issue number2
DOIs
StatePublished - Dec 2020
Externally publishedYes

Keywords

  • amyloid beta
  • astrocytes-neurons cross talk
  • extracellular vesicles
  • inflammation

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