APH1, PEN2, and Nicastrin increase Aβ levels and γ-secretase activity

Laura Marlow, Rosa M. Canet, Sharie J. Haugabook, John A. Hardy, Debomoy Lahiri, Kumar Sambamurti

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

A major component of the amyloid plaque core in Alzheimer's disease (AD) is the 40-42-residue amyloid β peptide (Aβ). Mutations linked to AD such as those in presenilins 1 (PS1) and 2 (PS2) invariably increase the longer Aβ42 species that forms neurotoxic oligomers. It is believed that PS1/2 constitute the catalytic subunit of the γ-secretase responsible for the final step in Aβ biogenesis. Recent genetic studies have identified a number of additional genes encoding APH1a, APH1b, PEN2, and Nicastrin proteins, which are part of the γ-secretase complex with PS1. Further, knockout studies using RNAi showed that these components are essential for γ-secretase activity. However, the nature of γ-secretase and how the aforementioned proteins regulate its activity are still incompletely understood. Here we present evidence that unlike PS1, overexpression of these proteins can increase the levels of Aβ, suggesting that these proteins are limiting for γ-secretase activity. In addition, our studies also suggest that the presenilin partners regulate the relative levels of Aβ40 and Aβ42.

Original languageEnglish
Pages (from-to)502-509
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume305
Issue number3
DOIs
StatePublished - Jun 6 2003

Fingerprint

Amyloid Precursor Protein Secretases
Presenilin-1
Presenilin-2
Amyloid
Alzheimer Disease
Presenilins
Proteins
Gene encoding
Amyloid Plaques
RNA Interference
Oligomers
Catalytic Domain
Mutation
Genes

Keywords

  • γ-Secretase
  • Amyloid
  • APH-1
  • APP
  • Intramembrane proteolysis
  • Nicastrin
  • Notch
  • PEN-2
  • Presenilin
  • Regulated proteolysis
  • Secretosome

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

APH1, PEN2, and Nicastrin increase Aβ levels and γ-secretase activity. / Marlow, Laura; Canet, Rosa M.; Haugabook, Sharie J.; Hardy, John A.; Lahiri, Debomoy; Sambamurti, Kumar.

In: Biochemical and Biophysical Research Communications, Vol. 305, No. 3, 06.06.2003, p. 502-509.

Research output: Contribution to journalArticle

Marlow, Laura ; Canet, Rosa M. ; Haugabook, Sharie J. ; Hardy, John A. ; Lahiri, Debomoy ; Sambamurti, Kumar. / APH1, PEN2, and Nicastrin increase Aβ levels and γ-secretase activity. In: Biochemical and Biophysical Research Communications. 2003 ; Vol. 305, No. 3. pp. 502-509.
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