title: Alternative processing of γ-secretase substrates in common forms of mild cognitive impairment and Alzheimer's disease: evidence for γ-secretase dysfunction.
abstract: OBJECTIVE
  The most common pathogenesis for familial Alzheimer's disease (FAD) involves misprocessing (or alternative processing) of the amyloid precursor protein (APP) by γ-secretase due to mutations of the presenilin 1 (PS1) gene. This misprocessing/alternative processing leads to an increase in the ratio of the level of a minor γ-secretase reaction product (Aβ42) to that of the major reaction product (Aβ40). Although no PS1 mutations are present, altered Aβ42/40 ratios are also observed in sporadic Alzheimer's disease (SAD), and these altered ratios apparently reflect deposition of Aβ42 as amyloid.
  
  
  METHODS
  Using immunoprecipitation-mass spectrometry with quantitative accuracy, we analyzed in the cerebrospinal fluid (CSF) of various clinical populations the peptide products generated by processing of not only APP but also an unrelated protein, alcadein (Alc). Alc undergoes metabolism by the identical APP α-secretases and γ-secretases, yielding a fragment that we have named p3-Alc(α) because of the parallel genesis of p3-Alc(α) peptides and the p3 fragment of APP. As with Aβ, both major and minor p3-Alc(α) s are generated. We studied the alternative processing of p3-Alc(α) in various clinical populations.
  
  
  RESULTS
  We previously reported that changes in the Aβ42/40 ratio showed covariance in a linear relationship with the levels of p3-Alc(α) [minor/major] ratio in media conditioned by cells expressing FAD-linked PS1 mutants. Here we studied the speciation of p3-Alc(α) in the CSF from 3 groups of human subjects (n = 158): elderly nondemented control subjects; mild cognitive impairment (MCI) subjects with a clinical dementia rating (CDR) of 0.5; SAD subjects with CDR of 1.0; and other neurological disease (OND) control subjects. The CSF minor p3-Alc(α) variant, p3-Alc(α) 38, was elevated (p < 0.05) in MCI subjects or SAD subjects, depending upon whether the data were pooled and analyzed as a single cohort or analyzed individually as 3 separate cohorts.
  
  
  CONCLUSIONS
  These results suggest that some SAD may involve alternative processing of multiple γ-secretase substrates, raising the possibility that the molecular pathogenesis of SAD might involve γ-secretase dysfunction.
authors.affiliation: Department of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Hata
authors.forename: Sayaka
authors.initials: S
authors.lastname: Fujishige
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Araki
authors.forename: Miyako
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Katsuya
authors.initials: K
authors.lastname: Urakami
authors.forename: Elaine
authors.initials: E
authors.lastname: Peskind
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Akatsu
authors.forename: Masahiko
authors.initials: M
authors.lastname: Araseki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Ralph N
authors.initials: RN
authors.lastname: Martins
authors.forename: Masahiro
authors.initials: M
authors.lastname: Maeda
authors.forename: Masaki
authors.initials: M
authors.lastname: Nishimura
authors.forename: Allan
authors.initials: A
authors.lastname: Levey
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Chung
authors.forename: Thomas
authors.initials: T
authors.lastname: Montine
authors.forename: James
authors.initials: J
authors.lastname: Leverenz
authors.forename: Anne
authors.initials: A
authors.lastname: Fagan
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
authors.forename: Randall
authors.initials: R
authors.lastname: Bateman
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.forename: Tohru
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nakaya
authors.forename: Sam
authors.initials: S
authors.lastname: Gandy
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications*; D053829:Amyloid Precursor Protein Secretases / Q000134:cerebrospinal fluid* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D016564:Amyloid beta-Protein Precursor / Q000134:cerebrospinal fluid; D003072:Cognition Disorders / Q000134:cerebrospinal fluid* / Q000209:etiology*; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D053719:Tandem Mass Spectrometry
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases