title: Pathophysiological amyloid concentrations induce sustained upregulation of readthrough acetylcholinesterase mediating anti-apoptotic effects.
abstract: Cholinergically differentiated SH-SY5Y neuroblastoma cells were treated with a pathophysiologically relevant, low (300 nM), and a high (3 μM) dose of amyloid beta 1-42 (Abeta) or 42-1 (revAbeta). At early (1 and 4h) and late (24h) time points, the pro- and anti-apoptotic factors--caspase-3 and p53, and B-cell lymphoma 2 protein (Bcl-2), respectively--were assessed together with lactate dehydrogenase (LDH) release as measure of cell viability and ATP levels as marker of mitochondrial activity. The low peptide dose significantly increased Bcl-2 and, time-delayed, caspase-3 and ATP levels, but barely impacted on LDH release, while the high concentration remarkably depressed Bcl-2 levels, depleted ATP and led to increased LDH release. We also monitored acetylcholinesterase (AChE) enzymatic activity and splice variant levels (tailed and readthrough AChE; AChE-T and AChE-R), and assessed choline acetyltransferase (ChAT) and high-affinity choline uptake (HACU). The low Abeta concentration drastically upregulated AChE-R and increased both ChAT and HACU, while the high dose caused cholinergic toxicity. We believe this study offers the first insight into the highly concentration-dependent effects of Abeta on cholinergic dynamics. In particular, it highlights the rescuing role of AChE-R as being, together with mitochondrial activity, involved in cholinergic adaptation to low doses of Abeta.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Biocentre N260, Max-von-Laue Straße 9, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Li
authors.forename: J
authors.initials: J
authors.lastname: Klein
authors.forename: M
authors.initials: M
authors.lastname: Zimmermann
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002794:Choline / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase; D002794:Choline