Amyloid-beta increases acetylcholinesterase expression in neuroblastoma cells by reducing enzyme degradation.
Amyloid-beta (Abeta) is the principal protein constituent of 'senile plaques' and is a suspected mediator in Alzheimer's disease (AD). Senile plaques also contain acetylcholinesterase (AChE; EC 3.1.1.7), which may have a role in promoting Alphabeta-toxicity. We have found that Alphabeta can affect AChE expression in a neuron-like line, the N1E.115 neuroblastoma cell. When 1 micro mAlphabeta 1-42 or 25-35 was added for 24 h to differentiating N1E.115 in culture, AChE activity increased 30-40% in adherent cells, and 100% or more in nonadherent cells. The changes in both tetrameric (G4) and monomeric (G1) AChE forms were comparable. Turnover studies indicated that the elevation of AChE activity reflected slowed AChE degradation rather than accelerated synthesis. With a similar time course, Alphabeta also increased the quantity of muscarinic receptors on the plasma membrane. Immunocytochemistry for a lysosomal membrane protein (LAMP-1) indicated no change in abundance or localization of lysosomes in treated cells. But decreased labeling by pH-sensitive fluorescent dye pointed to an impairment of lysosomal acidification. We consider that the alteration of AChE expression after Alphabeta-exposure could reflect lysosomal dysfunction, and might itself enhance Alphabeta-toxicity.
Hu
William
W
Department of Molecular Pharmacology, Mayo Medical School, Rochester, Minnesota, USA.
Gray
Noah W
NW
Brimijoin
Stephen
S
D000110:Acetylcholinesterase / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D002448:Cell Adhesion; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000201:enzymology; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007150:Immunohistochemistry; D007424:Intracellular Fluid / Q000201:enzymology; D051907:Lysosomal Membrane Proteins; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D018942:Macrolides; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D000900:Anti-Bacterial Agents; D015703:Antigens, CD; D004791:Enzyme Inhibitors; D051907:Lysosomal Membrane Proteins; D018942:Macrolides; D010446:Peptide Fragments; D011976:Receptors, Muscarinic; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); C040929:bafilomycin A1; D000110:Acetylcholinesterase