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Current Alzheimer Research
ISSN (Print): 1567-2050
ISSN (Online): 1875-5828
Epub Abstract Ahead of Print
DOI: 10.2174/1567205010666131212113218      Price:  $95

Selective Acetyl- and Butyrylcholinesterase Inhibitors Reduce amyloid- Ex Vivo Activation of Peripheral Chemo-Cytokines from Alzheimer’s Disease Subjects: Exploring the Cholinergic Anti-Inflammatory Pathway

Author(s): M Reale, M Di Nicola, L Velluto, C D’Angelo, E Costantini, DK Lahiri, MA Kamal, Yu Q-S and NH Greig
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Increasing evidence suggests that elevated production and/or reduced clearance of amyloid- peptide (A) drives the early pathogenesis of Alzheimer’s disease (AD). Asoluble oligomers trigger a neurotoxic cascade that leads to neuronaldysfunction, neurodegeneration and, ultimately, clinicaldementia. 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, is invariable hallmarks of the disease. The inter-relation between A, 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 A were significantly elevated in AD vs. HC subjects, and ACh showed a trend towards reduced levels. A challenge of PBMCs induced a greater release of inflammatory cytokines interleukin-1 (IL-1), monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-) 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 A as well as to phytohaemagglutinin (PHA) challenge, to allow preliminary analysis of the cellular and molecular pathways underpinning A-induced changes in cytokine expression. Asamyloid- precursor protein expression, and hence A,has been reported regulated by particularcytokines and anticholinesterases, the latter were evaluated on A- and PHA-induced chemo-cytokine 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
Drug Design and Development Section, Biomedical Research Center Room 05C 220, National Institute on Aging, 251 Bayview Blvd., Baltimore, MD 21224, USA