title: Changes in acetylcholinesterase expression are associated with altered presenilin-1 levels.
abstract: We have previously identified presenilin-1 (PS1), the active component of the γ-secretase complex, as an interacting protein of the amyloid-associated enzyme acetylcholinesterase (AChE). In this study, we have explored the consequences of AChE-PS1 interactions. Treatment of SH-SY5Y cells with the AChE-inhibitor tacrine decreased PS1 levels, in parallel with increase in the secretion of amyloid precursor protein APPα, whereas the cholinergic agonist carbachol had no effect on PS1. AChE knockdown with siRNA also decreased PS1 levels, while AChE overexpression exerted opposing effect. AChE-deficient also had decreased PS1. Mice administered with tacrine or donepezil displayed lower levels of brain PS1. However, sustained AChE inhibition failed to exert long-term effect on PS1. This limited duration of response may be due to AChE upregulation caused by chronic inhibition. Finally, we exposed SH-SY5Y cells to β-amyloid (Aβ)42 which triggered elevation of both AChE and PS1 levels. The Aβ42-induced PS1 increase was abolished by siRNA AChE pretreatment, suggesting that AChE may participate in the pathological feedback loop between PS1 and Aβ. Our results provide insight into AChE-amyloid interrelationships.
authors.affiliation: Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, Sant Joan d'Alacant, Alicante, Spain.
authors.forename: María-Ximena
authors.initials: MX
authors.lastname: Silveyra
authors.forename: María-Salud
authors.initials: MS
authors.lastname: García-Ayllón
authors.forename: Carol
authors.initials: C
authors.lastname: Serra-Basante
authors.forename: Valeria
authors.initials: V
authors.lastname: Mazzoni
authors.forename: María-Salud
authors.initials: MS
authors.lastname: García-Gutierrez
authors.forename: Jorge
authors.initials: J
authors.lastname: Manzanares
authors.forename: Janetta G
authors.initials: JG
authors.lastname: Culvenor
authors.forename: Javier
authors.initials: J
authors.lastname: Sáez-Valero
mesh_terms: D000110:Acetylcholinesterase / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000633:toxicity; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics / Q000502:physiology; D025461:Feedback, Physiological / Q000502:physiology; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity; D053764:Presenilin-1 / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D058851:GPI-Linked Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D034741:RNA, Small Interfering; C075222:amyloid beta-protein (1-42); C548244:ACHE protein, human; D000110:Acetylcholinesterase; C548245:Ache protein, mouse