Acetylcholinesterase modulates presenilin-1 levels and γ-secretase activity.
The cholinergic enzyme acetylcholinesterase (AChE) and the catalytic component of the γ-secretase complex, presenilin-1 (PS1), are known to interact. In this study, we investigate the consequences of AChE-PS1 interactions, particularly the influence of AChE in PS1 levels and γ-secretase activity. PS1 is able to co-immunoprecipitate all AChE variants (AChE-R and AChE-T) and molecular forms (tetramers and light subunits) present in the human brain. Overexpression of AChE-R or AChE-T, or their respective inactive mutants, all trigger an increase in PS1 protein levels. The AChE species capable of triggering the biggest increase in PS1 levels is a complex of AChE with the membrane anchoring subunit proline-rich membrane anchor (PRiMA), which restricts the localization of the resulting AChE tetramer to the outer plasma membrane. Incubation of cultured cells with soluble AChE demonstrates that AChE is able to increase PS1 at both the protein and transcript levels. However, the increase of PS1 caused by soluble AChE is accompanied by a decrease in γ-secretase activity as shown by the reduction of the processing of the amyloid-β protein precursor. This inhibitory effect of AChE on γ-secretase activity was also demonstrated by directly assessing accumulation of CTF-AβPP in cell-free membrane preparations incubated with AChE. Our data suggest that AChE may function as an inhibitor of γ-secretase activity.
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, Sant Joan d'Alacant, Spain Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Alicante, Spain.
Maria-Letizia
ML
Campanari
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, Sant Joan d'Alacant, Spain Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Alicante, Spain Unidad de Investigación, Hospital General Universitario de Elche, FISABIO, Elche, Spain.
María-Salud
MS
García-Ayllón
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Alicante, Spain Memory Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Olivia
O
Belbin
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, Sant Joan d'Alacant, Spain.
Joan
J
Galcerán
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Alicante, Spain Memory Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Alberto
A
Lleó
Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, Sant Joan d'Alacant, Spain Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Alicante, Spain.
Javier
J
Sáez-Valero
D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D016466:CHO Cells; D003412:Cricetulus; D006801:Humans; D047468:Immunoprecipitation; D009154:Mutation / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D053766:Presenilin-2 / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism; D014162:Transfection
C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D020033:Protein Isoforms; D012333:RNA, Messenger; D011950:Receptors, Cholinergic; D000110:Acetylcholinesterase; D053829:Amyloid Precursor Protein Secretases
Acetylcholinesterase; Alzheimer's disease; inhibitor; presenilin 1; γ-secretase