The pathogenic L392V mutation of presenilin 1 decreases the affinity to glycogen synthase kinase-3 beta

Determination of the effects of presenilin 1 (PSEN1) mutations, involved in autosomal dominant early-onset Alzheimer's disease (ADEOAD), on the intera ction between PSEN1 and binding proteins is essential to determine which in teractions are involved in Alzheimer's disease (AD) pathogenesis. The PSEN1 binding protein glycogen synthase kinase-3 beta (GSK-3 beta) has been cons idered as a key protein in AD pathogenesis since GSK-3 beta phosphorylates tau and hyperphosphorylated tau is a main component of neurofibrillary tang les associated to AD. We show here, using surface plasmonic resonance, that the pathogenic L392V mutation, identified in a large French ADEOAD pedigre e including 39 affected members, leads to a decreased affinity to GSK-3 bet a. We conclude therefore that the increase of affinity of PSEN1 to GSK-3 be ta reported in previous studies is not a common effect of pathogenic mutati ons associated to ADEOAD. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.