Presenilins and γ-Secretase: Structure, Function, and Role in Alzheimer Disease
- 1Center for Human Genetics, Leuven Institute for Neurodegenerative Diseases, KULeuven, 3000 Leuven, Belgium
- 2Department for Molecular and Developmental Genetics, VIB, 3000 Leuven, Belgium
- 3Department of Neuropathology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan
- 4Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
- Correspondence: mwolfe{at}rics.bwh.harvard.edu
Abstract
Presenilins were first discovered as sites of missense mutations responsible for early-onset Alzheimer disease (AD). The encoded multipass membrane proteins were subsequently found to be the catalytic components of γ-secretases, membrane-embedded aspartyl protease complexes responsible for generating the carboxyl terminus of the amyloid β-protein (Aβ) from the amyloid protein precursor (APP). The protease complex also cleaves a variety of other type I integral membrane proteins, most notably the Notch receptor, signaling from which is involved in many cell differentiation events. Although γ-secretase is a top target for developing disease-modifying AD therapeutics, interference with Notch signaling should be avoided. Compounds that alter Aβ production by γ-secretase without affecting Notch proteolysis and signaling have been identified and are currently at various stages in the drug development pipeline.
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