title: Association of a presenilin 1 S170F mutation with a novel Alzheimer disease molecular phenotype.
abstract: OBJECTIVE
  To report an ataxic variant of Alzheimer disease expressing a novel molecular phenotype.
  
  
  METHODS
  Description of a novel phenotype associated with a presenilin 1 mutation.
  
  
  METHODS
  The subject was an outpatient who was diagnosed at the local referral center.
  
  
  METHODS
  A 28-year-old man presented with psychiatric symptoms and cerebellar signs, followed by cognitive dysfunction. Severe beta-amyloid (Abeta) deposition was accompanied by neurofibrillary tangles and cell loss in the cerebral cortex and by Purkinje cell dendrite loss in the cerebellum. A presenilin 1 gene (PSEN1) S170F mutation was detected.
  
  
  METHODS
  We analyzed the processing of Abeta precursor protein in vitro as well as the Abeta species in brain tissue.
  
  
  RESULTS
  The PSEN1 S170F mutation induced a 3-fold increase of both secreted Abeta(42) and Abeta(40) species and a 60% increase of secreted Abeta precursor protein in transfected cells. Soluble and insoluble fractions isolated from brain tissue showed a prevalence of N-terminally truncated Abeta species ending at both residues 40 and 42.
  
  
  CONCLUSIONS
  These findings define a new Alzheimer disease molecular phenotype and support the concept that the phenotypic variability associated with PSEN1 mutations may be dictated by the Abeta aggregates' composition.
authors.affiliation: Department of Neurosciences, University of Genoa, Genoa, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Piccini
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Zanusso
authors.forename: Roberta
authors.initials: R
authors.lastname: Borghi
authors.forename: Cristiana
authors.initials: C
authors.lastname: Noviello
authors.forename: Salvatore
authors.initials: S
authors.lastname: Monaco
authors.forename: Roberta
authors.initials: R
authors.lastname: Russo
authors.forename: Gianluca
authors.initials: G
authors.lastname: Damonte
authors.forename: Andrea
authors.initials: A
authors.lastname: Armirotti
authors.forename: Matteo
authors.initials: M
authors.lastname: Gelati
authors.forename: Renzo
authors.initials: R
authors.lastname: Giordano
authors.forename: Pamela
authors.initials: P
authors.lastname: Zambenedetti
authors.forename: Claudio
authors.initials: C
authors.lastname: Russo
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
authors.forename: Massimo
authors.initials: M
authors.lastname: Tabaton
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D006801:Humans; D008297:Male; D009154:Mutation; D010446:Peptide Fragments / Q000378:metabolism; D010641:Phenotype; D010649:Phenylalanine / Q000235:genetics*; D053764:Presenilin-1 / Q000235:genetics*; D012694:Serine / Q000235:genetics*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D012694:Serine; D010649:Phenylalanine