| First Author | Muraleedharan A | Year | 2021 |
| Journal | Glia | Volume | 69 |
| Issue | 3 | Pages | 697-714 |
| PubMed ID | 33068318 | Mgi Jnum | J:303691 |
| Mgi Id | MGI:6509547 | Doi | 10.1002/glia.23921 |
| Citation | Muraleedharan A, et al. (2021) Protein kinase C eta is activated in reactive astrocytes of an Alzheimer's disease mouse model: Evidence for its immunoregulatory function in primary astrocytes. Glia 69(3):697-714 |
| abstractText | Alzheimer's disease (AD) is the primary cause of age-related dementia. Pathologically, AD is characterized by synaptic loss, the accumulation of beta-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 (PKCeta), an astrocyte-specific stress-activated and anti-apoptotic kinase, plays a role in reactive astrocytes. We demonstrate that PKCeta staining is highly enriched in cortical astrocytes in a disease-dependent manner and in the vicinity of amyloid-beta peptides plaques. Moreover, activation of PKCeta, as indicated by its increased phosphorylation levels, is exhibited mainly in cortical astrocytes derived from adult 5XFAD mice. PKCeta 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 PKCeta 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., TNFalpha, 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-PKCeta-PP2A signaling cascade functions as a negative feedback loop of NF-kappaB-induced IL-6 release in astrocytes. Thus, we identify PKCeta as a regulator of neuroinflammation in AD. |
