Protein kinase C eta is activated in reactive astrocytes of an Alzheimer's disease mouse model: Evidence for its immunoregulatory function in primary astrocytes.
Identifieur interne : 000066 ( Main/Exploration ); précédent : 000065; suivant : 000067Protein kinase C eta is activated in reactive astrocytes of an Alzheimer's disease mouse model: Evidence for its immunoregulatory function in primary astrocytes.
Auteurs : Amitha Muraleedharan [Israël] ; Noa Rotem-Dai [Israël] ; Itai Strominger [Israël] ; Nikhil Ponnoor Anto [Israël] ; Noah Isakov [Israël] ; Alon Monsonego [Israël] ; Etta Livneh [Israël]Source :
- Glia [ 1098-1136 ] ; 2020.
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.
DOI: 10.1002/glia.23921
PubMed: 33068318
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Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.</nlm:affiliation><country xml:lang="fr">Israël</country><wicri:regionArea>The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva</wicri:regionArea><wicri:noRegion>Beer-Sheva</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>The National Institute of Biotechnology in the Negev, Zlotowski Neuroscience Center, and Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.</nlm:affiliation><country xml:lang="fr">Israël</country><wicri:regionArea>The National Institute of Biotechnology in the Negev, Zlotowski Neuroscience Center, and Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva</wicri:regionArea><wicri:noRegion>Beer-Sheva</wicri:noRegion></affiliation></author><author><name sortKey="Livneh, Etta" sort="Livneh, Etta" uniqKey="Livneh E" first="Etta" last="Livneh">Etta Livneh</name><affiliation wicri:level="1"><nlm:affiliation>The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.</nlm:affiliation><country xml:lang="fr">Israël</country><wicri:regionArea>The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva</wicri:regionArea><wicri:noRegion>Beer-Sheva</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2020">2020</date><idno type="RBID">pubmed:33068318</idno><idno type="pmid">33068318</idno><idno type="doi">10.1002/glia.23921</idno><idno type="wicri:Area/Main/Corpus">000011</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000011</idno><idno 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Beer-Sheva, Israel.</nlm:affiliation><country xml:lang="fr">Israël</country><wicri:regionArea>The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva</wicri:regionArea><wicri:noRegion>Beer-Sheva</wicri:noRegion></affiliation></author><author><name sortKey="Strominger, Itai" sort="Strominger, Itai" uniqKey="Strominger I" first="Itai" last="Strominger">Itai Strominger</name><affiliation wicri:level="1"><nlm:affiliation>The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.</nlm:affiliation><country xml:lang="fr">Israël</country><wicri:regionArea>The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva</wicri:regionArea><wicri:noRegion>Beer-Sheva</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>The National Institute of Biotechnology in the Negev, Zlotowski Neuroscience Center, and Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.</nlm:affiliation><country xml:lang="fr">Israël</country><wicri:regionArea>The National Institute of Biotechnology in the Negev, Zlotowski Neuroscience Center, and Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva</wicri:regionArea><wicri:noRegion>Beer-Sheva</wicri:noRegion></affiliation></author><author><name sortKey="Anto, Nikhil Ponnoor" sort="Anto, Nikhil Ponnoor" uniqKey="Anto N" first="Nikhil Ponnoor" last="Anto">Nikhil Ponnoor Anto</name><affiliation wicri:level="1"><nlm:affiliation>The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.</nlm:affiliation><country xml:lang="fr">Israël</country><wicri:regionArea>The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva</wicri:regionArea><wicri:noRegion>Beer-Sheva</wicri:noRegion></affiliation></author><author><name sortKey="Isakov, Noah" sort="Isakov, Noah" uniqKey="Isakov N" first="Noah" last="Isakov">Noah Isakov</name><affiliation wicri:level="1"><nlm:affiliation>The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.</nlm:affiliation><country xml:lang="fr">Israël</country><wicri:regionArea>The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva</wicri:regionArea><wicri:noRegion>Beer-Sheva</wicri:noRegion></affiliation></author><author><name sortKey="Monsonego, Alon" sort="Monsonego, Alon" uniqKey="Monsonego A" first="Alon" last="Monsonego">Alon Monsonego</name><affiliation wicri:level="1"><nlm:affiliation>The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.</nlm:affiliation><country xml:lang="fr">Israël</country><wicri:regionArea>The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva</wicri:regionArea><wicri:noRegion>Beer-Sheva</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>The National Institute of Biotechnology in the Negev, Zlotowski Neuroscience Center, and Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.</nlm:affiliation><country xml:lang="fr">Israël</country><wicri:regionArea>The National Institute of Biotechnology in the Negev, Zlotowski Neuroscience Center, and Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva</wicri:regionArea><wicri:noRegion>Beer-Sheva</wicri:noRegion></affiliation></author><author><name sortKey="Livneh, Etta" sort="Livneh, Etta" uniqKey="Livneh E" first="Etta" last="Livneh">Etta Livneh</name><affiliation wicri:level="1"><nlm:affiliation>The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.</nlm:affiliation><country xml:lang="fr">Israël</country><wicri:regionArea>The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva</wicri:regionArea><wicri:noRegion>Beer-Sheva</wicri:noRegion></affiliation></author></analytic><series><title level="j">Glia</title><idno type="eISSN">1098-1136</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><pubmed><MedlineCitation Status="Publisher" Owner="NLM"><PMID Version="1">33068318</PMID><DateRevised><Year>2020</Year><Month>10</Month><Day>17</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1098-1136</ISSN><JournalIssue CitedMedium="Internet"><PubDate><Year>2020</Year><Month>Oct</Month><Day>17</Day></PubDate></JournalIssue><Title>Glia</Title><ISOAbbreviation>Glia</ISOAbbreviation></Journal><ArticleTitle>Protein kinase C eta is activated in reactive astrocytes of an Alzheimer's disease mouse model: Evidence for its immunoregulatory function in primary astrocytes.</ArticleTitle><ELocationID EIdType="doi" ValidYN="Y">10.1002/glia.23921</ELocationID><Abstract><AbstractText>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.</AbstractText><CopyrightInformation>© 2020 Wiley Periodicals LLC.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Muraleedharan</LastName><ForeName>Amitha</ForeName><Initials>A</Initials><Identifier Source="ORCID">https://orcid.org/0000-0002-5825-6514</Identifier><AffiliationInfo><Affiliation>The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>The National Institute of Biotechnology in the Negev, Zlotowski Neuroscience Center, and Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rotem-Dai</LastName><ForeName>Noa</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Strominger</LastName><ForeName>Itai</ForeName><Initials>I</Initials><AffiliationInfo><Affiliation>The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>The National Institute of Biotechnology in the Negev, Zlotowski Neuroscience Center, and Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Anto</LastName><ForeName>Nikhil Ponnoor</ForeName><Initials>NP</Initials><AffiliationInfo><Affiliation>The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Isakov</LastName><ForeName>Noah</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Monsonego</LastName><ForeName>Alon</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>The National Institute of Biotechnology in the Negev, Zlotowski Neuroscience Center, and Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Livneh</LastName><ForeName>Etta</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>1864/16</GrantID><Agency>Israel Science Foundation</Agency><Country></Country></Grant><Grant><GrantID>684/14</GrantID><Agency>Israel Science Foundation</Agency><Country></Country></Grant><Grant><Agency>Litwin and Gural Family foundations</Agency><Country></Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>10</Month><Day>17</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Glia</MedlineTA><NlmUniqueID>8806785</NlmUniqueID><ISSNLinking>0894-1491</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Alzheimer's disease</Keyword><Keyword MajorTopicYN="N">IL-6</Keyword><Keyword MajorTopicYN="N">PKCη</Keyword><Keyword MajorTopicYN="N">astrocytes</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2020</Year><Month>03</Month><Day>28</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2020</Year><Month>09</Month><Day>24</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2020</Year><Month>10</Month><Day>01</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2020</Year><Month>10</Month><Day>17</Day><Hour>12</Hour><Minute>6</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2020</Year><Month>10</Month><Day>18</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>10</Month><Day>18</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>aheadofprint</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">33068318</ArticleId><ArticleId IdType="doi">10.1002/glia.23921</ArticleId></ArticleIdList><ReferenceList><Title>REFERENCES</Title><Reference><Citation>Alfonso, S. 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