Fibroblasts from FAD-linked presenilin 1 mutations display a normal unfolded protein response but overproduce Aβ42 in response to tunicamycin

• Main Authors: Alessandra Piccini, Anna Fassio, Elena Pasqualetto, Antonella Vitali, Roberta Borghi, Daniela Palmieri, Benedetta Nacmias, Sandro Sorbi, Roberto Sitia, Massimo Tabaton
• Format: Article
• Language: English
• Published: Elsevier 2004-03-01
• Series: Neurobiology of Disease
• Subjects: Presenilin; Alzheimer's disease; Endoplasmic reticulum; Amyloid; Unfolding protein response; Primary fibroblasts
• Online Access: http://www.sciencedirect.com/science/article/pii/S096999610300250X

Many patients affected by early onset familial Alzheimer's disease (FAD), carry mutations in the presenilin 1 (PS1) gene. Since it has been suggested that FAD-linked PS1 mutations impair the unfolded protein response (UPR) due to endoplasmic reticulum (ER) stress, we analyzed the UPR and amyloid β-protein processing in fibroblasts bearing various PS1 mutations. Neither in normal conditions nor after induction of ER stress with DTT or tunicamycin were the mRNA levels of UPR-responsive genes (BiP and PDI) significantly different in control and FAD fibroblasts. DTT, which blocked APP transport to the Golgi, caused a 30% decrease of secreted Aβ42 in wild type and PS1 mutant fibroblasts. In contrast, tunicamycin, which allowed exit of APP from the ER, increased secreted Aβ42 only in PS1 mutant fibroblasts. Our findings suggest that, although the UPR is active in fibroblasts from FAD patients, mutant PS1 may selectively increase Aβ42 secretion when N-glycosylation is impaired.