A presenilin 1 mutation associated with familial frontotemporal dementia inhibits γ-secretase cleavage of APP and notch

Zareen Amtul, Patrick A. Lewis, Sian Piper, Richard Crook, Matt Baker, Kirk Findlay, Andrew Singleton, Marion Hogg, Linda Younkin, Steven G. Younkin, John Hardy, Michael Hutton, Bradley F. Boeve, David Tang-Wai, Todd E. Golde

Research output: Contribution to journalArticlepeer-review

86 Scopus citations

Abstract

A novel presenilin 1 mutation insR352 associated with a frontal temporal dementia phenotype has been identified (E. A. Rogaeva et al. 2001 Neurology 57 621-625). This mutation does not increase Aβ42 levels but instead acts as dominant negative presenilin decreasing amyloid β protein (Aβ) production by inhibiting γ-secretase cleavage of the Aβ precursor. The distinct clinical phenotype associated with this mutation suggests that chronic partial inhibition of γ-secretase activity may result in neurodegeneration.

Original languageEnglish (US)
Pages (from-to)269-273
Number of pages5
JournalNeurobiology of Disease
Volume9
Issue number2
DOIs
StatePublished - Mar 2002

ASJC Scopus subject areas

  • Neurology

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