Biological Effects of Four PSEN1 Gene Mutations Causing Alzheimer Disease With Spastic Paraparesis and Cotton Wool Plaques

We describe the biological consequences on PSEN1 exons 8 or 9 splicing and Aβ peptides production of four PSEN1 mutations associated with a phenotypic variant of Alzheimer disease, which includes cotton wool plaques and spastic paraparesis (CWP/SP). Two of these mutations (c.869-22_869-23ins18 and c.871A>C, p.T291P) are novel mutations located in intron 8 and exon 9, respectively. The c.869-22_869-23ins18 mutation caused exon 9 skipping whereas the c.871A>C (p.T291P) mutation showed only a modest effect on exon 9 skipping. The previously reported E280G and P264L mutations, located in exon 8, had no effect on mRNA splicing. Infection of cells with mutant T291P, E280G, or P264L cDNAs caused a variable increase in secreted Aβ42. We conclude that none of the previously proposed mechanisms, i.e. exceptionally large increases in secreted Aβ42 levels or loss of PSEN1 exons 8 or 9, provides complete explanation of the CWP/SP phenotype. © 2006 Wiley-Liss, Inc.