Identification of Peptides Binding to Presenilin 1 by Screening of Random Peptide Display Libraries

Abstract

The genes encoding presenilin 1 (PS-1) on chromosome 14 and presenilin 2 (PS-2) on chromosome 1 have been identified as major causal genes for early onset familial Alzheimer’s disease (FAD) (Sherington et al. 1995; Levy-Lahad et al., 1995). Genetic studies showed that early onset FAD linked to chromosomes 14 and 1 is caused by mis-sence mutations in PS-1 and PS-2 (Sherington et al. 1995; Levy-Lahad et ai., 1995). Patients with this form of FAD revealed increased levels of highly amyloidogenic species of amyloid beta protein (Aβ_1–42 and Aβ_1–43) in plasma and cerebral amyloid depositions (Scheuner et al. 1996; Mann et al. 1996). In addition, presenilins were shown to form stable complexes with amyloid precursor protein (APP) (Weidemann et al. 1997). Although mechanism of Aβ _1–42 and Aβ _1–43 accumulation in FAD is not clear the results above suggest that PS-1 and PS-2 are directly or indirectly involved in the APP metabolism and amyloid formation. Recently PS-2 gene was shown to contribute to apoptosis induced by trophic factor withdrawal, β-amyloid, and T cell receptor-induced apoptosis (Wolozin et al. 1996; Vito et al., 1996). Light and electron microscopy studies suggest predominant localization of PS-1 to the nuclear membrane, endoplasmic reticulum (ER)-Golgi compartments and coated transport vesicles (Cook et al., 1996; Kovacset al., 1996; Lahet al., 1997).