Li_2013_Neurosci_240_349

Cholinergically differentiated SH-SY5Y neuroblastoma cells were treated with a pathophysiologically relevant, low (300 nM), and a high (3 muM) 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.