Acetylcholinesterase Modulates Presenilin-1 Levels and gamma-Secretase Activity
Por:
Campanari, ML, Garcia-Ayllon, MS, Belbin, O, Galceran, J, Lleo, A, Saez-Valero, J
Publicada:
1 ene 2014
Resumen:
The cholinergic enzyme acetylcholinesterase (AChE) and the catalytic component of the gamma-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 gamma-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 gamma-secretase activity as shown by the reduction of the processing of the amyloid-beta protein precursor. This inhibitory effect of AChE on gamma-secretase activity was also demonstrated by directly assessing accumulation of CTF-A beta PP in cell-free membrane preparations incubated with AChE. Our data suggest that AChE may function as an inhibitor of gamma-secretase activity.
Filiaciones:
Campanari, ML:
Univ Miguel Hernandez, CSIC, Inst Neurociencias Alicante, E-03550 Sant Joan dAlacant, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Alicante, Spain
Garcia-Ayllon, MS:
Univ Miguel Hernandez, CSIC, Inst Neurociencias Alicante, E-03550 Sant Joan dAlacant, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Alicante, Spain
Hosp Gen Univ Elche, FISABIO, Unidad Invest, Elche, Spain
Belbin, O:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Alicante, Spain
Hosp Santa Creu & Sant Pau, Dept Neurol, Memory Unit, Barcelona, Spain
Galceran, J:
Univ Miguel Hernandez, CSIC, Inst Neurociencias Alicante, E-03550 Sant Joan dAlacant, Spain
Lleo, A:
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Alicante, Spain
Hosp Santa Creu & Sant Pau, Dept Neurol, Memory Unit, Barcelona, Spain
Saez-Valero, J:
Univ Miguel Hernandez, CSIC, Inst Neurociencias Alicante, E-03550 Sant Joan dAlacant, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Alicante, Spain
Open Access
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