Protein kinase C eta is activated in reactive astrocytes of an Alzheimer's disease mouse model: Evidence for its immunoregulatory function in primary astrocytes

Amitha Muraleedharan, Noa Rotem-Dai, Itai Strominger, Nikhil Ponnoor Anto, Noah Isakov, Alon Monsonego, Etta Livneh

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Alzheimer's disease (AD) is the primary cause of age-related dementia. Pathologically, AD is characterized by synaptic loss, the accumulation of β-amyloid peptides and neurofibrillary tangles, glial activation, and neuroinflammation. Whereas extensive studies focused on neurons and activation of microglia in AD, the role of astrocytes has not been well-characterized. Protein kinase C (PKC) was also implicated in AD; however, its role in astrocyte activation was not elucidated. Using the 5XFAD mouse model of AD, we show that PKC-eta (PKCη), an astrocyte-specific stress-activated and anti-apoptotic kinase, plays a role in reactive astrocytes. We demonstrate that PKCη staining is highly enriched in cortical astrocytes in a disease-dependent manner and in the vicinity of amyloid-β peptides plaques. Moreover, activation of PKCη, as indicated by its increased phosphorylation levels, is exhibited mainly in cortical astrocytes derived from adult 5XFAD mice. PKCη activation was associated with elevated levels of reactive astrocytic markers and upregulation of the pro-inflammatory cytokine interleukin 6 (IL-6) compared to littermate controls. Notably, inhibiting the kinase activity of PKCη in 5XFAD astrocyte cultures markedly increased the levels of secreted IL-6—a phenomenon that was also observed in wild-type astrocytes stimulated by inflammatory cytokines (e.g., TNFα, IL-1). Similar increase in the release of IL-6 was also observed upon inhibition of either the mammalian target of rapamycin (mTOR) or the protein phosphatase 2A (PP2A). Our findings suggest that the mTOR-PKCη-PP2A signaling cascade functions as a negative feedback loop of NF-κB-induced IL-6 release in astrocytes. Thus, we identify PKCη as a regulator of neuroinflammation in AD.

Original languageEnglish
Pages (from-to)697-714
Number of pages18
JournalGLIA
Volume69
Issue number3
DOIs
StatePublished - 1 Mar 2021

Keywords

  • Alzheimer's disease
  • IL-6
  • PKCη
  • astrocytes

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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