Title:Gamma Secretase as an Important Drug Target for Management of
Alzheimer’s Disease: A Comprehensive Review
Volume: 24
Issue: 2
Author(s): Fady Tadros Hakem, Youstina Farid Fouad and Reem K. Arafa*
Affiliation:
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, 12578,
Cairo, Egypt
- Drug Design
and Discovery Lab, Zewail City of Science and Technology, 12578, Cairo, Egypt
Keywords:
Gamma-secretase, Alzheimer’s disease, APP, Notch, Presenilin, Amyloid-β plaques.
Abstract: Alzheimer’s disease (AD) is a neurological disease that affects the memory. AD has
been attributed to the aggregations of amyloid-β (Aβ) peptides which result in the formation of
plaques that block the neuron-transferring process done by the brain memory cells. These plaques
are formed upon cleavage of Amyloid Precursor Protein (APP) by Gamma-Secretase (GS). GS
protein has around 141 substrates, the important two are APP and Notch. Considering one of the
hot spots in AD research, we focused on GS and its relation to AD. Moreover, a lot of research
was done on beta-secretase and drugs were developed to target it however, few drugs are established
for GS. GS contains four subunits: Presenilin (PS), PEN-2, Nicastrin, and APH-1. The catalytic
subunit is PS, which contains the active site for substrate binding, as well as the allosteric
and docking sites. Both PEN-2 and APH-1 are regulators for the stability and activity of GS. Nicastrin,
helps the substrates bind to the PS. Additionally, the role of the immuno-protein named
“IFITM3” and how it affects the immune system and its relation to AD is presented. GS is one of
the most studied proteins with many developed candidates as inhibitors (GSI) and modulators (GSM).
Examples of GSI are Semagacestat and Avagacestat while GSM includes E2012; which inhibits
the cleavage activity of GS. In this report, each of the four subunits of GS is described in detail,
along with the interactions between GS and its inhibitors or modulators. In addition, the
FDA-approved drugs are enlisted.
