10,12 This could be a novel therapeutic strategy to target Aβ neurotoxicity in AD. Presenilin APP mutations result in only a small proportion of autosomal dominant inherited types of AD, which is why there have been so many linkage CP-868596 cell line studies of other loci with FAD. The observation of linkage with chromosomal region 14q in some FAD families eventually led to the discovery of a novel gene, namely presenilin 1 (PS1).73-76 The first PS1 mutation

associated with FAD was reported in 1995.73,77,78 Since then about 120 kinds of PS1 mutation have been reported in about 260 families around the world. Almost all of the reported PS1 mutations are missense and give rise to the Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical substitution of a single amino acid. So far, only two splicing defect mutations have been reported79,82; these change the topography of the protein in membranes. In addition, the mutations are most frequently observed in exon 5 (28 mutations), exon 7 (23 mutations), and exon 8 (20 mutations). Mutation in the intron was also found to be able to produce AD.83 Of the 120 PS1 mutations reported, the majority were only found in a single AD family. The most frequently observed is the AD-associated PS1 mutation on codon 206 (Gly206Ala), and was Inhibitors,research,lifescience,medical found in 18 families. The other common mutations are Met146Len in 12

families, Glu280Ala in 12 families, His163 Arg in 10 families, and Pro264Leu in 8 families. Almost Inhibitors,research,lifescience,medical all of the PS1 mutations were found to cause early-onset AD. However, PS1 mutation on codon 318 (Glu318Gly) was found in 6 families with SAD and 4 families with FAD, and even in normal subjects. 84,85 Therefore, this mutation is called a partial pathogenetic factor. The gene for presenilin 2 (PS2) was Inhibitors,research,lifescience,medical first identified on chromosome 1 in the public nucleotide sequence database, and has an overall 62% homology to PS1.86,87

The first mutation in PS2 found to associate with FAD was identified in a German family by linkage studies.86,87 Thereafter, more than eight kinds of missense mutations in PS2 were found to cause AD. However, the PS2 mutations do not only Rutecarpine produce FAD and late-onset AD.74,88 There is one known case of a PS2 mutation with apparent nonpenetrance in an asymptomatic octogenarian transmitter of the disease.74 Currently, most researchers believe that the major pathological role for mutant PS1 and PS2 in AD comes from their capacity to facilitate production of amyloidogenic Aβ42 peptides.67,89 This “gain-of-function” hypothesis has been evidenced by many biochemical findings and transgenic studies.89,90 Presenilin is a conserved polytopic membrane-spanning protein family consisting of PSI, a 463-amino acid polypeptide, and PS2, a 448-amino acid polypeptide.