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Presenilin 1 Modulates Acetylcholinesterase Trafficking and Maturation.

International journal of molecular sciences (2023-01-22)
María-Ángeles Cortés-Gómez, Víctor M Barberá, Jordi Alom, Javier Sáez-Valero, María-Salud García-Ayllón
ABSTRACT

In Alzheimer's disease (AD), the reduction in acetylcholinesterase (AChE) enzymatic activity is not paralleled with changes in its protein levels, suggesting the presence of a considerable enzymatically inactive pool in the brain. In the present study, we validated previous findings, and, since inactive forms could result from post-translational modifications, we analyzed the glycosylation of AChE by lectin binding in brain samples from sporadic and familial AD (sAD and fAD). Most of the enzymatically active AChE was bound to lectins Canavalia ensiformis (Con A) and Lens culinaris agglutinin (LCA) that recognize terminal mannoses, whereas Western blot assays showed a very low percentage of AChE protein being recognized by the lectin. This indicates that active and inactive forms of AChE vary in their glycosylation pattern, particularly in the presence of terminal mannoses in active ones. Moreover, sAD subjects showed reduced binding to terminal mannoses compared to non-demented controls, while, for fAD patients that carry mutations in the PSEN1 gene, the binding was higher. The role of presenilin-1 (PS1) in modulating AChE glycosylation was then studied in a cellular model that overexpresses PS1 (CHO-PS1). In CHO-PS1 cells, binding to LCA indicates that AChE displays more terminal mannoses in oligosaccharides with a fucosylated core. Immunocytochemical assays also demonstrated increased presence of AChE in the trans-Golgi. Moreover, AChE enzymatic activity was higher in plasmatic membrane of CHO-PS1 cells. Thus, our results indicate that PS1 modulates trafficking and maturation of AChE in Golgi regions favoring the presence of active forms in the membrane.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Lectin from Triticum vulgaris (wheat), agarose conjugate, saline suspension
Sigma-Aldrich
Concanavalin A from Canavalia ensiformis (Jack bean), Sepharose conjugate, buffered aqueous suspension
Sigma-Aldrich
Bovine Serum Albumin, heat shock fraction, protease free, essentially globulin free, pH 7, ≥98%
Sigma-Aldrich
Lectin from Lens culinaris (lentil), Sepharose conjugate, saline suspension