Feb 9, 2012

Presenilins and γ-secretase: structure, function, and role in Alzheimer Disease

Cold Spring Harbor Perspectives in Medicine
Bart De StrooperMichael S Wolfe

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.

  • References164
  • Citations137
  • References164
  • Citations137

Citations

Mentioned in this Paper

Drug Development
Presenilins
Familial Alzheimer Disease (FAD)
Receptors, Notch
Protein Digestion
APP protein, human
Aspartic Acid Endopeptidases
Notch
Structure-Activity Relationship
Complex (molecular entity)

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