title: Functional variability in butyrylcholinesterase activity regulates intrathecal cytokine and astroglial biomarker profiles in patients with Alzheimer's disease.
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.
authors.affiliation: Division of Alzheimer Neurobiology Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden. Taher.Darreh-Shori@ki.se
authors.forename: Taher
authors.initials: T
authors.lastname: Darreh-Shori
authors.forename: Swetha
authors.initials: S
authors.lastname: Vijayaraghavan
authors.forename: Shahin
authors.initials: S
authors.lastname: Aeinehband
authors.forename: Fredrik
authors.initials: F
authors.lastname: Piehl
authors.forename: Rickard P F
authors.initials: RP
authors.lastname: Lindblom
authors.forename: Bo
authors.initials: B
authors.lastname: Nilsson
authors.forename: Kristina N
authors.initials: KN
authors.lastname: Ekdahl
authors.forename: Bengt
authors.initials: B
authors.lastname: Långström
authors.forename: Ove
authors.initials: O
authors.lastname: Almkvist
authors.forename: Agneta
authors.initials: A
authors.lastname: Nordberg
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000110:Acetylcholinesterase / Q000378:metabolism; D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000150:complications / Q000000981:diagnostic imaging / Q000473:pathology*; D000814:Aniline Compounds; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002091:Butyrylcholinesterase / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000209:etiology; D003165:Complement System Proteins / Q000378:metabolism; D016207:Cytokines / Q000134:cerebrospinal fluid*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D019788:Fluorodeoxyglucose F18; D005904:Glial Fibrillary Acidic Protein / Q000134:cerebrospinal fluid; D006801:Humans; D008297:Male; D008609:Mental Status Schedule; D008840:Microfilament Proteins; D009483:Neuropsychological Tests; D020641:Polymorphism, Single Nucleotide; D011877:Radionuclide Imaging; D064568:S100 Calcium Binding Protein beta Subunit / Q000134:cerebrospinal fluid; D013844:Thiazoles
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; C112986:AIF1 protein, human; D000814:Aniline Compounds; D002135:Calcium-Binding Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D064568:S100 Calcium Binding Protein beta Subunit; D013844:Thiazoles; D019788:Fluorodeoxyglucose F18; D003165:Complement System Proteins; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D000109:Acetylcholine
keywords: Alzheimer's disease; Astrocytes; BCHE genotype; Butyrylcholinesterase; Cholinergic anti-inflammatory pathway; Cholinoceptive cells; Complement system; Glial fibrillary acidic protein; Microglia; S100B