In search of γ-secretase: Presenilin at the cutting edge
Year: 2000
Type: article
Abstract: The effort to solve Alzheimer's disease (AD) has led to a salutary intersection between the desire to prevent a major health problem and the fundamental study of membrane protein biology. It has become apparent in the last few years that a compelling strategy to treat and prevent AD may involve understanding how certain integral membrane proteins undergo unusual proteolytic cleavages within their transmembrane domains, and then inhibiting this process pharmacologically. The substrate of interest in AD is the βamyloid precursor protein (APP), but several other proteins apparently are cleaved by a highly similar or identical proteolytic activity within their respective transmembrane domains, including the Notch family of cell-surface receptors required for cell fate determination (1) and the Ire1 proteins that initiate signaling in the unfolded protein response pathway (2). The unknown protease that affects the intramembranous cleavage of APP (and perhaps Notch and Ire1) is referred to as γ-secretase (reviewed in ref. 3). Its identity is being actively sought because it is the second of two proteases that sequentially cleave APP to release a small fragment called the amyloid β-protein (Aβ). [The other protease, β-secretase, recently has been cloned (4–8).] Progressive accumulation of Aβ in brain regions subserving memory and cognition is an early, invariant, and necessary step in the pathogenesis of AD. For these reasons, β- and γ-secretases are considered important targets for the development of effective therapeutics to treat AD.
Authors: Dennis J. Selkoe, Michael S. Wolfe
Institutions: Brigham and Women's Hospital, Harvard University
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2086701519