title: Relative ratio and level of amyloid-β 42 surrogate in cerebrospinal fluid of familial Alzheimer disease patients with presenilin 1 mutations.
abstract: BACKGROUND
  Presenilin 1 (PS1) mutations associated with familial Alzheimer disease (FAD) generally increase the amyloid-β 42 (Aβ42) to Aβ40 ratio secreted in cultured cells. Some of these mutants reduce the secretion of Aβ40 rather than increase that of Aβ42. Since it has been difficult to estimate Aβ42 secretion in brains of PS1-FAD patients due to substantial Aβ42 accumulation, it remains unknown whether the enhanced Aβ42 to Aβ40 ratio in brains of FAD patients is caused by elevated Aβ42 secretion or by reduced secretion of Aβ40.
  
  
  OBJECTIVE
  Cerebrospinal fluids (CSF) of PS1-FAD patients and neurological control patients (controls) were collected. Levels of CSF amyloid precursor-like protein-1-derived Aβ-like peptide (APL1β), including APL1β28, an Aβ42 surrogate marker, were quantified by liquid chromatography tandem mass spectrometry, and Aβ42 secretion in the brain was estimated.
  
  
  RESULTS
  The relative ratio of CSF APL1β28 to total APL1β was higher in PS1-FAD patients than in controls. Importantly, CSF APL1β28 was not significantly higher. However, C-terminally shorter CSF APL1β25 and APL1β27 were significantly lower in PS1-FAD patients and, as expected, so were CSF Aβ40 and Aβ42.
  
  
  CONCLUSIONS
  A higher relative ratio of the CSF Aβ42 surrogate in PS1-FAD patients is not due to its increase in CSF, suggesting that massive Aβ42 accumulation in the PS1-FAD brain occurs without an apparent increase in Aβ42 secretion.
authors.affiliation: Neuropsychiatry and Neurochemistry, Division of Internal Medicine, Department of Integrated Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Tagami
authors.forename: Masayasu
authors.initials: M
authors.lastname: Okochi
authors.forename: Kanta
authors.initials: K
authors.lastname: Yanagida
authors.forename: Takashi
authors.initials: T
authors.lastname: Kodama
authors.forename: Tetsuaki
authors.initials: T
authors.lastname: Arai
authors.forename: Ryozo
authors.initials: R
authors.lastname: Kuwano
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ikeuchi
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takeda
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D002853:Chromatography, Liquid; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053764:Presenilin-1 / Q000235:genetics*; D053719:Tandem Mass Spectrometry
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; C508853:PSEN1 protein, human; D053764:Presenilin-1