Gamma-secretase substrates

Gamma-secretase substrates are a diverse group of over 100 type I transmembrane proteins that undergo intramembrane proteolysis by the gamma-secretase aspartyl protease complex [1]. The most clinically significant substrate is the amyloid precursor protein (APP), which, when cleaved, releases amyloid-beta peptides that are central to the pathology of Alzheimer's disease [2]. Another vital substrate is the Notch receptor family (Notch 1-4), which releases an intracellular domain upon cleavage that acts as a transcription factor to regulate cell fate, differentiation, and development [3]. Other substrates include E-cadherin, CD44, and ErbB4, highlighting the enzyme's role in various signaling pathways [1]. Because many substrates have essential physiological roles, broad inhibition of gamma-secretase often leads to severe side effects, particularly gastrointestinal toxicity due to Notch inhibition [4]. Consequently, therapeutic development has shifted from non-selective inhibitors to gamma-secretase modulators that specifically target APP processing while sparing other critical substrates [5]. In oncology, however, the inhibition of Notch processing is the primary therapeutic goal for treating certain cancers and desmoid tumors [6].

Other names

Gamma-secretase cleavage productsType I transmembrane protein substratesγ-secretase substratesGamma-secretase targetsGamma-secretase substrate proteins

Inhibition or modulation of the gamma-secretase enzyme complex to prevent or alter the intramembrane proteolysis of substrate proteins like APP and Notch.