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

Increasing evidence suggests that elevated production and/or reduced clearance of amyloid-beta peptide (A beta) drives the early pathogenesis of Alzheimer's disease (AD). A beta 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 A beta, 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 beta were significantly elevated in AD vs. HC subjects, and ACh showed a trend towards reduced levels. A beta challenge of PBMCs induced a greater release of inflammatory cytokines interleukin-1 beta (IL-1 beta), monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha) 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 beta as well as to phytohaemagglutinin (PHA) challenge, to allow preliminary analysis of the cellular and molecular pathways underpinning A beta-induced changes in cytokine expression. As amyloid-beta precursor protein expression, and hence A beta, has been reported regulated by particular cytokines and anticholinesterases, the latter were evaluated on A beta- 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.