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Functional variabil...
Functional variability in butyrylcholinesterase activity regulates intrathecal cytokine and astroglial biomarker profiles in patients with Alzheimer's disease
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- Darreh-Shori, Taher (author)
- Karolinska Institutet
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- Vijayaraghavan, Swetha (author)
- Karolinska Institutet
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- Aeinehband, Shahin (author)
- Karolinska Institutet
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- Lindblom, Rickard P F (author)
- Karolinska Institutet,Uppsala universitet,Thoraxkirurgi,Karolinska University Hospital Solna
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- Lindblom, Rickard P. F. (author)
- Karolinska University Hospital Solna
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- Nilsson, Bo (author)
- Uppsala universitet,Klinisk immunologi,Uppsala University
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- Nilsson Ekdahl, Kristina (author)
- Uppsala universitet,Linnéuniversitetet,Institutionen för kemi och biomedicin (KOB),Uppsala University,Linnaeus Ctr Biomat Chem, BMC,Klinisk immunologi
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- Långström, Bengt (author)
- Uppsala universitet,Fysikalisk-organisk kemi,Uppsala University;Imperial College, UK;Odense University Hospital, University of Southern Denmark, Denmark
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- Almkvist, Ove (author)
- Stockholms universitet,Psykologiska institutionen,Karolinska Institutet, Sweden,Karolinska Institutet;Stockholm University
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- Nordberg, Agneta (author)
- Karolinska Institutet
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(creator_code:org_t)
- Elsevier BV, 2013
- 2013
- English.
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In: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 34:11, s. 2465-2481
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Abstract
Subject headings
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- Butyrylcholinesterase (BuChE) activity is associated with activated astrocytes in Alzheimer's disease brain. The BuChE-K variant exhibits 30%-60% reduced acetylcholine (ACh) hydrolyzing capacity. Considering the increasing evidence of an immune-regulatory role of ACh, we investigated if genetic heterogeneity in BuChE affects cerebrospinal fluid (CSF) biomarkers of inflammation and cholinoceptive glial function. Alzheimer's disease patients (n = 179) were BCHE-K-genotyped. Proteomic and enzymatic analyses were performed on CSF and/or plasma. BuChE genotype was linked with differential CSF levels of glial fibrillary acidic protein, S100B, interleukin-1 beta, and tumor necrosis factor (TNF)-alpha. BCHE-K noncarriers displayed 100%-150% higher glial fibrillary acidic protein and 64%-110% higher S100B than BCHE-K carriers, who, in contrast, had 40%-80% higher interleukin-1b and 21%-27% higher TNF-alpha compared with noncarriers. A high level of CSF BuChE enzymatic phenotype also significantly correlated with higher CSF levels of astroglial markers and several factors of the innate complement system, but lower levels of proinflammatory cytokines. These individuals also displayed beneficial paraclinical and clinical findings, such as high cerebral glucose utilization, low beta-amyloid load, and less severe progression of clinical symptoms. In vitro analysis on human astrocytes confirmed the involvement of a regulated BuChE status in the astroglial responses to TNF-alpha and ACh. Histochemical analysis in a rat model of nerve injury-induced neuroinflammation, showed focal assembly of astroglial cells in proximity of BuChE-immunolabeled sites. In conclusion, these results suggest that BuChE enzymatic activity plays an important role in regulating intrinsic inflammation and activity of cholinoceptive glial cells and that this might be of clinical relevance. The dissociation between astroglial markers and inflammatory cytokines indicates that a proper activation and maintenance of astroglial function is a beneficial response, rather than a disease-driving mechanism. Further studies are needed to explore the therapeutic potential of manipulating BuChE activity or astroglial functional status. (C) 2013 Elsevier Inc. All rights reserved.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Geriatrik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Geriatrics (hsv//eng)
- SAMHÄLLSVETENSKAP -- Psykologi (hsv//swe)
- SOCIAL SCIENCES -- Psychology (hsv//eng)
Keyword
- Butyrylcholinesterase
- Astrocytes
- Microglia
- Cholinoceptive cells
- Alzheimer's disease
- BCHE genotype
- Glial fibrillary acidic protein
- S100B
- Complement system
- Cholinergic anti-inflammatory pathway
- Biomedical Sciences
- Biomedicinsk vetenskap
Publication and Content Type
- ref (subject category)
- art (subject category)
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Darreh-Shori, Ta ...
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Vijayaraghavan, ...
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Aeinehband, Shah ...
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Lindblom, Rickar ...
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Lindblom, Rickar ...
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Nilsson, Bo
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Nilsson Ekdahl, ...
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Långström, Bengt
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Almkvist, Ove
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Nordberg, Agneta
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- MEDICAL AND HEALTH SCIENCES
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and Basic Medicine
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SOCIAL SCIENCES
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Neurobiology of ...
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Linnaeus University
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Stockholm University
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Uppsala University
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Karolinska Institutet