A Novel PSEN1 K311R Mutation Discovered in Chinese Families with Late-Onset Alzheimer's Disease Affects Amyloid-β Production and Tau Phosphorylation

Background: Presenilin-1 (PSEN1) is the most frequently mutated gene in familial Alzheimer's disease (AD), whereas only several novel mutations have been reported in China and functional studies were seldom conducted. Objective: We describe a novel PSEN1 K311R mutation in two Chinese families with late-onset AD and its functional impact on amyloid-beta protein precursor (A beta PP) processing and tau phosphorylation. Methods: The mutation was detected by direct sequencing of PSEN1 exon 9. HEK293 cells stably expressing wild-type APP695 (HEK293-APP695(wt)) were transfected with plasmids containing human wild-type PSEN1, PSEN1 K311R mutation, and PSEN1 E280A mutation to compare the K311R mutation's effects on A beta PP processing with other groups. In addition, each group of cells were co-transfected with plasmids harboring PSEN1 and human wild-type MAPT complementary DNA to study the mutation's impacts on tau phosphorylation. Results: The K311R mutation was detected in probands of two late-onset AD families. Expression of the K311R or E280A mutation increased amyloid-beta (A beta)(42) levels but decreased A beta(40) levels, resulting in an overall increase in the A beta(42)/A beta(40) ratio compared to those in wild-type PSEN1 transfected cells (p < 0.05). The K311R or E280A mutation also increased the levels of phosphorylated tau compared to wild-type PSEN1 (p < 0.05). Conclusion: The K311R mutation might contribute to AD pathogenesis by overproducing toxic A beta species and enhancing tau phosphorylation. Further in-depth studies are needed to decipher the pathogenic mechanisms of the K311R mutation in terms of A beta PP cleavage, tau phosphorylation, and other presenilin-1 mediated functional pathways.