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Functional variability in butyrylcholinesterase activity regulates intrathecal cytokine and astroglial biomarker profiles in patients with Alzheimer's disease
- Source :
- Darreh-Shori, T, Vijayaraghavan, S, Aeinehband, S, Piehl, F, Lindblom, R P F, Nilsson, B, Ekdahl, K N, Roland Långström, B, Almkvist, O & Nordberg, A 2013, ' Functional variability in butyrylcholinesterase activity regulates intrathecal cytokine and astroglial biomarker profiles in patients with Alzheimer's disease ', Neurobiology of Aging, vol. 34, no. 11, pp. 2465-81 . https://doi.org/10.1016/j.neurobiolaging.2013.04.027
- Publication Year :
- 2013
- Publisher :
- Elsevier BV, 2013.
-
Abstract
- 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-1β, and tumor necrosis factor (TNF)-α. 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-1β and 21%-27% higher TNF-α 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 β-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-α 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.
- Subjects :
- Male
Aging
medicine.medical_treatment
Neuropsychological Tests
chemistry.chemical_compound
Cells, Cultured
Butyrylcholinesterase
Aniline Compounds
Glial fibrillary acidic protein
biology
Microglia
General Neuroscience
Microfilament Proteins
Acetylcholinesterase
DNA-Binding Proteins
Cytokine
medicine.anatomical_structure
Cytokines
Biomarker (medicine)
Female
Alzheimer's disease
Acetylcholine
medicine.drug
medicine.medical_specialty
S100 Calcium Binding Protein beta Subunit
Polymorphism, Single Nucleotide
Alzheimer Disease
Fluorodeoxyglucose F18
Internal medicine
Glial Fibrillary Acidic Protein
medicine
Humans
Radionuclide Imaging
Aged
Calcium-Binding Proteins
Complement System Proteins
medicine.disease
Thiazoles
Endocrinology
chemistry
Astrocytes
biology.protein
Neurology (clinical)
Geriatrics and Gerontology
Cognition Disorders
Mental Status Schedule
Developmental Biology
Subjects
Details
- ISSN :
- 01974580
- Volume :
- 34
- Database :
- OpenAIRE
- Journal :
- Neurobiology of Aging
- Accession number :
- edsair.doi.dedup.....0832515231654ef58e5055ac91872476