title: A Novel PSEN1 K311R Mutation Discovered in Chinese Families with Late-Onset Alzheimer's Disease Affects Amyloid-β Production and Tau Phosphorylation.
abstract: 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.
  
  
  
  We describe a novel PSEN1 K311R mutation in two Chinese families with late-onset AD and its functional impact on amyloid-β protein precursor (AβPP) processing and tau phosphorylation.
  
  
  
  The mutation was detected by direct sequencing of PSEN1 exon 9. HEK293 cells stably expressing wild-type APP695 (HEK293-APP695wt) were transfected with plasmids containing human wild-type PSEN1, PSEN1 K311R mutation, and PSEN1 E280A mutation to compare the K311R mutation's effects on AβPP 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.
  
  
  
  The K311R mutation was detected in probands of two late-onset AD families. Expression of the K311R or E280A mutation increased amyloid-β (Aβ)42 levels but decreased Aβ40 levels, resulting in an overall increase in the Aβ42/Aβ40 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).
  
  
  
  The K311R mutation might contribute to AD pathogenesis by overproducing toxic Aβ species and enhancing tau phosphorylation. Further in-depth studies are needed to decipher the pathogenic mechanisms of the K311R mutation in terms of AβPP cleavage, tau phosphorylation, and other presenilin-1 mediated functional pathways.
authors.affiliation: Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Dong
authors.affiliation: Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, P.R. China.|Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing, P.R. China.|Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, P.R. China.|Key Neurodegenerative Laboratory of the Ministry of Education of the People's Republic of China, Beijing, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Qin
authors.affiliation: Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, P.R. China.|Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, P.R. China.|Key Neurodegenerative Laboratory of the Ministry of Education of the People's Republic of China, Beijing, P.R. China.
authors.forename: Cuibai
authors.initials: C
authors.lastname: Wei
authors.affiliation: Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, P.R. China.|Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing, P.R. China.|Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, P.R. China.|Key Neurodegenerative Laboratory of the Ministry of Education of the People's Republic of China, Beijing, P.R. China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, P.R. China.|Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing, P.R. China.|Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, P.R. China.|Key Neurodegenerative Laboratory of the Ministry of Education of the People's Republic of China, Beijing, P.R. China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Jia
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D044466:Asian People / Q000235:genetics; D002681:China; D005190:Family; D017809:Fatal Outcome; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation; D053764:Presenilin-1 / Q000235:genetics*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C054369:MAPT protein, human; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D053829:Amyloid Precursor Protein Secretases
keywords: Amyloid-β; familial Alzheimer’s disease; mutation; presenilin; tau