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Expression and Differential Responsiveness of Central Nervous System Glial Cell Populations to the Acute Phase Protein Serum Amyloid A.

ABSTRACT: Acute-phase response is a systemic reaction to environmental/inflammatory insults and involves hepatic production of acute-phase proteins, including serum amyloid A (SAA). Extrahepatically, SAA immunoreactivity is found in axonal myelin sheaths of cortex in Alzheimer's disease and multiple sclerosis (MS), although its cellular origin is unclear. We examined the responses of cultured rat cortical astrocytes, microglia and oligodendrocyte precursor cells (OPCs) to master pro-inflammatory cytokine tumour necrosis factor (TNF)-? and lipopolysaccaride (LPS). TNF-? time-dependently increased Saa1 (but not Saa3) mRNA expression in purified microglia, enriched astrocytes, and OPCs (as did LPS for microglia and astrocytes). Astrocytes depleted of microglia were markedly less responsive to TNF-? and LPS, even after re-addition of microglia. Microglia and enriched astrocytes showed complementary Saa1 expression profiles following TNF-? or LPS challenge, being higher in microglia with TNF-? and higher in astrocytes with LPS. Recombinant human apo-SAA stimulated production of both inflammatory mediators and its own mRNA in microglia and enriched, but not microglia-depleted astrocytes. Co-ultramicronized palmitoylethanolamide/luteolin, an established anti-inflammatory/ neuroprotective agent, reduced Saa1 expression in OPCs subjected to TNF-? treatment. These last data, together with past findings suggest that co-ultramicronized palmitoylethanolamide/luteolin may be a novel approach in the treatment of inflammatory demyelinating disorders like MS.

SUBMITTER: Barbierato M

PROVIDER: S-EPMC5610307 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Expression and Differential Responsiveness of Central Nervous System Glial Cell Populations to the Acute Phase Protein Serum Amyloid A.

Barbierato Massimo M Borri Mila M Facci Laura L Zusso Morena M Skaper Stephen D SD Giusti Pietro P

Scientific reports 20170922 1

Acute-phase response is a systemic reaction to environmental/inflammatory insults and involves hepatic production of acute-phase proteins, including serum amyloid A (SAA). Extrahepatically, SAA immunoreactivity is found in axonal myelin sheaths of cortex in Alzheimer's disease and multiple sclerosis (MS), although its cellular origin is unclear. We examined the responses of cultured rat cortical astrocytes, microglia and oligodendrocyte precursor cells (OPCs) to master pro-inflammatory cytokine ...[more]

PMID: 28939905

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Project description:Importance:Recent studies found that the concentration of amyloid-? (A?) fluctuates with the sleep-wake cycle. Although the amplitude of this day/night pattern attenuates with age and amyloid deposition, to our knowledge, the association of A? kinetics (ie, production, turnover, and clearance) with this oscillation has not been studied. Objective:To determine the association between A? kinetics, age, amyloid levels, and the A? day/night pattern in humans. Design, Setting, and Participants:We measured A? concentrations and kinetics in 77 adults aged 60 to 87 years with and without amyloid deposition by a novel precise mass spectrometry method at the Washington University School of Medicine in St Louis, Missouri. We compared findings of 2 orthogonal methods, enzyme-linked immunosorbent assay and mass spectrometry, to validate the day/night patterns and determine more precise estimates of the cosinor parameters. In vivo labeling of central nervous system proteins with stable isotopically labeled leucine was performed, and kinetics of A?40 and A?42 were measured. Interventions:Serial cerebrospinal fluid collection via indwelling lumbar catheter over 36 to 48 hours before, during, and after in vivo labeling, with a 9-hour primed constant infusion of 13C6-leucine. Main Outcomes and Measures:The amplitude, linear increase, and other cosinor measures of each participant's serial cerebrospinal fluid A? concentrations and A? turnover rates. Results:Of the 77 participants studied, 46 (59.7%) were men, and the mean (range) age was 72.6 (60.4-87.7) years. Day/night patterns in A? concentrations were more sharply defined by the precise mass spectrometry method than by enzyme-linked immunosorbent assay (mean difference of SD of residuals: A?40, -7.42 pM; P?<?.001; A?42, -3.72 pM; P?<?.001). Amyloid deposition diminished day/night amplitude and linear increase of A?42 but not of A?40. Increased age diminished day/night amplitude of both A?40 and A?42. After controlling for amyloid deposition, amplitude of A?40 was positively associated with production rates (r?=?0.42; P?<?.001), while the linear rise was associated with turnover rates (r?=?0.28; P?<?.05). The amplitude and linear rise of A?42 were both associated with turnover (r?=?-0.38; P?<?.001) and production (r?=?0.238; P?<?.05) rates. Conclusions and Relevance:Amyloid deposition is associated with premature loss of normal A?42 day/night patterns in older adults, suggesting the previously reported effects of age and amyloid on A?42 amplitude at least partially affect each other. Production and turnover rates suggest that day/night A? patterns are modulated by both production and clearance mechanisms active in sleep-wake cycles and that amyloid deposition may impair normal circadian patterns. These findings may be important for the designs of future secondary prevention trials for Alzheimer disease.

Dataset Information

Expression and Differential Responsiveness of Central Nervous System Glial Cell Populations to the Acute Phase Protein Serum Amyloid A.

Publications

Expression and Differential Responsiveness of Central Nervous System Glial Cell Populations to the Acute Phase Protein Serum Amyloid A.

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