title: Multiple γ-secretase product peptides are coordinately increased in concentration in the cerebrospinal fluid of a subpopulation of sporadic Alzheimer's disease subjects.
abstract: BACKGROUND
  Alcadeinα (Alcα) is a neuronal membrane protein that colocalizes with the Alzheimer's amyloid-β precursor protein (APP). Successive cleavage of APP by β- and γ-secretases generates the aggregatable amyloid-β peptide (Aβ), while cleavage of APP or Alcα by α- and γ-secretases generates non-aggregatable p3 or p3-Alcα peptides. Aβ and p3-Alcα can be recovered from human cerebrospinal fluid (CSF). We have previously reported alternative processing of APP and Alcα in the CSF of some patients with sporadic mild cognitive impairment (MCI) and AD (SAD).
  
  
  RESULTS
  Using the sandwich enzyme-linked immunosorbent assay (ELISA) system that detects total p3-Alcα, we determined levels of total p3-Alcα in CSF from subjects in one of four diagnostic categories (elderly controls, MCI, SAD, or other neurological disease) derived from three independent cohorts. Levels of Aβ40 correlated with levels of total p3-Alcα in all cohorts.
  
  
  CONCLUSIONS
  We confirm that Aβ40 is the most abundant Aβ species, and we propose a model in which CSF p3-Alcα can serve as a either (1) a nonaggregatable surrogate marker for γ-secretase activity; (2) as a marker for clearance of transmembrane domain peptides derived from integral protein catabolism; or (3) both. We propose the specification of an MCI/SAD endophenotype characterized by co-elevation of levels of both CSF p3-Alcα and Aβ40, and we propose that subjects in this category might be especially responsive to therapeutics aimed at modulation of γ-secretase function and/or transmembrane domain peptide clearance. These peptides may also be used to monitor the efficacy of therapeutics that target these steps in Aβ metabolism.
authors.affiliation: Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Hata
authors.forename: Miyako
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Yi
authors.initials: Y
authors.lastname: Piao
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ikeuchi
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fagan
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.forename: Randall
authors.initials: R
authors.lastname: Bateman
authors.forename: Hamid R
authors.initials: HR
authors.lastname: Sohrabi
authors.forename: Ralph N
authors.initials: RN
authors.lastname: Martins
authors.forename: Sam
authors.initials: S
authors.lastname: Gandy
authors.forename: Katsuya
authors.initials: K
authors.lastname: Urakami
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000134:cerebrospinal fluid* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D016564:Amyloid beta-Protein Precursor / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; D053829:Amyloid Precursor Protein Secretases