gamma-Secretase in Alzheimer's disease

Alzheimer's disease: changing activity of critical enzyme offers therapeutic option Drugs that only affect the activity of an enzyme called gamma-secretase but do not entirely block its function could provide a safer therapeutic option for preventing the build-up of toxic proteins in the brain linked to AD. Dr. Ji-Yeun Hur from Memorial Sloan Kettering Cancer Center, New York, USA, discusses the functions of gamma-secretase, which include cleaving amyloid precursor proteins into smaller fragments that can aggregate to form sticky plaques, and reviews attempts to develop therapies directed against the enzyme. Early drug candidates proved too toxic because they blocked all functions of gamma-secretase including desirable functions, leading to side effects. Newer drug strategies have focused on changing how gamma-secretase processes Alzheimer's-related proteins without disrupting its other physiological functions. A better understanding of gamma-secretase's complex structure and various functions could inform those strategies. Alzheimer's disease (AD) is caused by synaptic and neuronal loss in the brain. One of the characteristic hallmarks of AD is senile plaques containing amyloid beta-peptide (A beta). A beta is produced from amyloid precursor protein (APP) by sequential proteolytic cleavages by beta-secretase and gamma-secretase, and the polymerization of A beta into amyloid plaques is thought to be a key pathogenic event in AD. Since gamma-secretase mediates the final cleavage that liberates A beta, gamma-secretase has been widely studied as a potential drug target for the treatment of AD. gamma-Secretase is a transmembrane protein complex containing presenilin, nicastrin, Aph-1, and Pen-2, which are sufficient for gamma-secretase activity. gamma-Secretase cleaves >140 substrates, including APP and Notch. Previously, gamma-secretase inhibitors (GSIs) were shown to cause side effects in clinical trials due to the inhibition of Notch signaling. Therefore, more specific regulation or modulation of gamma-secretase is needed. In recent years, gamma-secretase modulators (GSMs) have been developed. To modulate gamma-secretase and to understand its complex biology, finding the binding sites of GSIs and GSMs on gamma-secretase as well as identifying transiently binding gamma-secretase modulatory proteins have been of great interest. In this review, decades of findings on gamma-secretase in AD are discussed.