title: Selective acetyl- and butyrylcholinesterase inhibitors reduce amyloid-β ex vivo activation of peripheral chemo-cytokines from Alzheimer's disease subjects: exploring the cholinergic anti-inflammatory pathway.
abstract: Increasing evidence suggests that elevated production and/or reduced clearance of amyloid-β peptide (Aβ) drives the early pathogenesis of Alzheimer's disease (AD). Aβ soluble oligomers trigger a neurotoxic cascade that leads to neuronal dysfunction, neurodegeneration and, ultimately, clinical dementia. Inflammation, both within brain and systemically, together with a deficiency in the neurotransmitter acetylcholine (ACh) that underpinned the development of anticholinesterases for AD symptomatic treatment, are invariable hallmarks of the disease. The inter-relation between Aβ, inflammation and cholinergic signaling is complex, with each feeding back onto the others to drive disease progression. To elucidate these interactions plasma samples and peripheral blood mononuclear cells (PBMCs) were evaluated from healthy controls (HC) and AD patients. Plasma levels of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and Aβ were significantly elevated in AD vs. HC subjects, and ACh showed a trend towards reduced levels. Aβ challenge of PBMCs induced a greater release of inflammatory cytokines interleukin-1β (IL-1β), monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-α) from AD vs. HC subjects, with IL-10 being similarly affected. THP-1 monocytic cells, a cell culture counterpart of PBMCs and brain microglial cells, responded similarly to Aβ as well as to phytohaemagglutinin (PHA) challenge, to allow preliminary analysis of the cellular and molecular pathways underpinning Aβ-induced changes in cytokine expression. As amyloid-β precursor protein expression, and hence Aβ, has been reported regulated by particular cytokines and anticholinesterases, the latter were evaluated on Aβ- and PHA-induced chemocytokine expression. Co-incubation with selective AChE/BuChE inhibitors, (-)-phenserine (AChE) and (-)-cymserine analogues (BuChE), mitigated the rise in cytokine levels and suggest that augmentation of the cholinergic anti-inflammatory pathway may prove valuable in AD.
authors.forename: Marcella
authors.initials: M
authors.lastname: Reale
authors.forename: Marta
authors.initials: M
authors.lastname: Di Nicola
authors.forename: Lucia
authors.initials: L
authors.lastname: Velluto
authors.forename: Chiara
authors.initials: C
authors.lastname: D'Angelo
authors.forename: Erica
authors.initials: E
authors.lastname: Costantini
authors.forename: Debomoy K
authors.initials: DK
authors.lastname: Lahiri
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Kamal
authors.forename: Qian-sheng
authors.initials: QS
authors.lastname: Yu
authors.affiliation: Dept. of Experimental and Clinical Sciences, Unit ofImmunodiagnostic and Molecular Pathology, University "G. D'Annunzio", N.P.D., Ed. C, III lev., Via dei Vestini, 31, 66123 Chieti, Italy. mreale@unich.it.
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000276:immunology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D002091:Butyrylcholinesterase / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000502:physiology; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D018925:Chemokines; D002800:Cholinesterase Inhibitors; D016207:Cytokines; C508609:IL10 protein, human; C508585:IL1B protein, human; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase