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Neuroinflammation and A? accumulation linked to systemic inflammation are decreased by genetic PKR down-regulation.

ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disorder, marked by senile plaques composed of amyloid-? (A?) peptide, neurofibrillary tangles, neuronal loss and neuroinflammation. Previous works have suggested that systemic inflammation could contribute to neuroinflammation and enhanced A? cerebral concentrations. The molecular pathways leading to these events are not fully understood. PKR is a pro-apoptotic kinase that can trigger inflammation and accumulates in the brain and cerebrospinal fluid of AD patients. The goal of the present study was to assess if LPS-induced neuroinflammation and A? production could be altered by genetic PKR down regulation. The results show that, in the hippocampus of LPS-injected wild type mice, neuroinflammation, cytokine release and A? production are significantly increased and not in LPS-treated PKR knock-out mice. In addition BACE1 and activated STAT3 levels, a putative transcriptional regulator of BACE1, were not found increased in the brain of PKR knock-out mice as observed in wild type mice. Using PET imaging, the decrease of hippocampal metabolism induced by systemic LPS was not observed in LPS-treated PKR knock-out mice. Altogether, these findings demonstrate that PKR plays a major role in brain changes induced by LPS and could be a valid target to modulate neuroinflammation and A? production.

SUBMITTER: Carret-Rebillat AS

PROVIDER: S-EPMC4330547 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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Neuroinflammation and Aβ accumulation linked to systemic inflammation are decreased by genetic PKR down-regulation.

Carret-Rebillat Anne-Sophie AS Pace Clarisse C Gourmaud Sarah S Ravasi Laura L Montagne-Stora Samantha S Longueville Sophie S Tible Marion M Sudol Erika E Chang Raymond Chuen-Chung RC Paquet Claire C Mouton-Liger François F Hugon Jacques J

Scientific reports 20150217

Alzheimer's disease (AD) is a neurodegenerative disorder, marked by senile plaques composed of amyloid-β (Aβ) peptide, neurofibrillary tangles, neuronal loss and neuroinflammation. Previous works have suggested that systemic inflammation could contribute to neuroinflammation and enhanced Aβ cerebral concentrations. The molecular pathways leading to these events are not fully understood. PKR is a pro-apoptotic kinase that can trigger inflammation and accumulates in the brain and cerebrospinal flu ...[more]

PMID: 25687824

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Project description:BackgroundWe recently found that brain tissue from patients with type-2 diabetes (T2D) and cognitive impairment contains deposits of amylin, an amyloidogenic hormone synthesized and co-secreted with insulin by pancreatic ?-cells. Amylin deposition is promoted by chronic hypersecretion of amylin (hyperamylinemia), which is common in humans with obesity or pre-diabetic insulin resistance. Human amylin oligomerizes quickly when oversecreted, which is toxic, induces inflammation in pancreatic islets and contributes to the development of T2D. Here, we tested the hypothesis that accumulation of oligomerized amylin affects brain function.MethodsIn contrast to amylin from humans, rodent amylin is neither amyloidogenic nor cytotoxic. We exploited this fact by comparing rats overexpressing human amylin in the pancreas (HIP rats) with their littermate rats which express only wild-type (WT) non-amyloidogenic rodent amylin. Cage activity, rotarod and novel object recognition tests were performed on animals nine months of age or older. Amylin deposition in the brain was documented by immunohistochemistry, and western blot. We also measured neuroinflammation by immunohistochemistry, quantitative real-time PCR and cytokine protein levels.ResultsCompared to WT rats, HIP rats show i) reduced exploratory drive, ii) impaired recognition memory and iii) no ability to improve the performance on the rotarod. The development of neurological deficits is associated with amylin accumulation in the brain. The level of oligomerized amylin in supernatant fractions and pellets from brain homogenates is almost double in HIP rats compared with WT littermates (P?<?0.05). Large amylin deposits (>50 ?m diameter) were also occasionally seen in HIP rat brains. Accumulation of oligomerized amylin alters the brain structure at the molecular level. Immunohistochemistry analysis with an ED1 antibody indicates possible activated microglia/macrophages which are clustering in areas positive for amylin infiltration. Multiple inflammatory markers are expressed in HIP rat brains as opposed to WT rats, confirming that amylin deposition in the brain induces a neuroinflammatory response.ConclusionsHyperamylinemia promotes accumulation of oligomerized amylin in the brain leading to neurological deficits through an oligomerized amylin-mediated inflammatory response. Additional studies are needed to determine whether brain amylin accumulation may predispose to diabetic brain injury and cognitive decline.

Project description:BackgroundNaturally occurring variation in Membrane-bound O-acyltransferase domain-containing 7 (MBOAT7), encoding for an enzyme involved in phosphatidylinositol acyl-chain remodelling, has been associated with fatty liver and hepatic disorders. Here, we examined the relationship between hepatic Mboat7 down-regulation and fat accumulation.MethodsHepatic MBOAT7 expression was surveyed in 119 obese individuals and in experimental models. MBOAT7 was acutely silenced by antisense oligonucleotides in C57Bl/6 mice, and by CRISPR/Cas9 in HepG2 hepatocytes.FindingsIn obese individuals, hepatic MBOAT7 mRNA decreased from normal liver to steatohepatitis, independently of diabetes, inflammation and MBOAT7 genotype. Hepatic MBOAT7 levels were reduced in murine models of fatty liver, and by hyper-insulinemia. In wild-type mice, Mboat7 was down-regulated by refeeding and insulin, concomitantly with insulin signalling activation. Acute hepatic Mboat7 silencing promoted hepatic steatosis in vivo and enhanced expression of fatty acid transporter Fatp1. MBOAT7 deletion in hepatocytes reduced the incorporation of arachidonic acid into phosphatidylinositol, consistently with decreased enzymatic activity, determining the accumulation of saturated triglycerides, enhanced lipogenesis and FATP1 expression, while FATP1 deletion rescued the phenotype.InterpretationMBOAT7 down-regulation by hyper-insulinemia contributes to hepatic fat accumulation, impairing phosphatidylinositol remodelling and up-regulating FATP1.FundingLV was supported by MyFirst Grant AIRC n.16888, Ricerca Finalizzata Ministero della Salute RF-2016-02,364,358, Ricerca corrente Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico; LV and AG received funding from the European Union Programme Horizon 2020 (No. 777,377) for the project LITMUS-"Liver Investigation: Testing Marker Utility in Steatohepatitis". MM was supported by Fondazione Italiana per lo Studio del Fegato (AISF) 'Mario Coppo' fellowship.

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Neuroinflammation and A? accumulation linked to systemic inflammation are decreased by genetic PKR down-regulation.

Publications

Neuroinflammation and Aβ accumulation linked to systemic inflammation are decreased by genetic PKR down-regulation.

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