Familial Alzheimer's disease presenilin 1 mutations cause alterations in the conformation of presenilin and interactions with amyloid precursor protein

Oksana Berezovska, Alberto Lleo, Lauren D. Herl, Matthew P. Frosch, Edward A. Stern, Brian J. Bacskai, Bradley T. Hyman

Research output: Contribution to journalArticlepeer-review

134 Scopus citations

Abstract

Presenilin 1 (PS1) is a critical component of the γ-secretase complex, an enzymatic activity that cleaves amyloid β(Aβ) from the amyloid precursor protein (APP). More than 100 mutations spread throughout the PS1 molecule are linked to autosomal dominant familial Alzheimer's disease (FAD). All of these mutations lead to a similar phenotype: an increased ratio of Aβ42 to Aβ40 increased plaque deposition, and early age of onset. We use a recently developed microscopy approach, fluorescence lifetime imaging microscopy, to monitor the relative molecular distance between PS1 N and C termini in intact cells. We show that FAD-linked missense mutations located near the N and C termini, in the mid-region of PS1, and the exon 9 deletion mutation all change the spatial relationship between PS1 N and C termini in a similar way, increasing proximity of the two epitopes. This effect is opposite of that observed by treatment with Aβ42- lowering nonsteroidal anti-inflammatory drugs (NSAIDs) (Lleo et al., 2004b). Accordingly, treatment of M146L PS1-overexpressing neurons with high-dose NSAIDs somewhat offsets the conformational change associated with the mutation. Moreover, by monitoring the relative distance between a PS1 loop epitope and the APP C terminus, we demonstrate that the FAD PS1 mutations are also associated with a consistent change in the configuration of the PS1-APP complex. The nonpathogenic E318G PS1 polymorphism had no effect on PS1 N terminus-C terminus proximity or PS1-APP interactions. We propose that the conformational change we observed may therefore provide a shared molecular mechanism for FAD pathogenesis caused by a wide range of PS1 mutations.

Original languageEnglish
Pages (from-to)3009-3017
Number of pages9
JournalJournal of Neuroscience
Volume25
Issue number11
DOIs
StatePublished - 16 Mar 2005
Externally publishedYes

Keywords

  • Amyloid precursor protein
  • Amyloid β peptide
  • Familial Alzheimer's disease
  • Fluorescence lifetime imaging microscopy (FLIM)
  • Presenilin 1
  • γ-secretase

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