Presenilin: Acts as the catalytic subunit responsible for the proteolytic activity.
Nicastrin: Functions as a substrate receptor, aiding in substrate recognition and binding.
APH-1: Involved in the stabilization and assembly of the complex.
PEN-2: Essential for the endoproteolysis of presenilin and activation of the complex.
Gamma secretase mediates the cleavage of its substrates within the lipid bilayer of cellular membranes. The process begins with the recognition and binding of the substrate to the complex, primarily facilitated by nicastrin. Once bound, the substrate undergoes sequential proteolytic cleavage by presenilin. This cleavage releases the intracellular and extracellular domains of the substrate, which can then participate in various cellular signaling pathways.
The gamma secretase complex is critically involved in the pathogenesis of
Alzheimer's disease (AD). The cleavage of the amyloid precursor protein (APP) by gamma secretase generates
amyloid-beta (Aβ) peptides, which can aggregate to form the amyloid plaques characteristic of AD. Mutations in the genes encoding presenilin-1 and presenilin-2 are linked to early-onset familial Alzheimer's disease, highlighting the significance of gamma secretase in neurodegeneration.
Given its role in AD, gamma secretase is an attractive target for therapeutic intervention. However, developing effective
gamma secretase inhibitors has been challenging due to the enzyme's involvement in essential cellular functions, such as Notch signaling. Inhibition of gamma secretase can lead to adverse effects, including impaired immune function and gastrointestinal toxicity. Thus, therapeutic strategies are now focusing on developing
selective modulators that can specifically reduce amyloid-beta production without affecting other substrates.
In histology, the gamma secretase complex can be studied using various techniques, including
immunohistochemistry and
immunofluorescence. These methods allow for the visualization of the localization and expression levels of the complex's subunits in tissue samples. Additionally,
in situ hybridization can be employed to detect the mRNA expression of gamma secretase components in specific cell types within tissues.
Future research on the gamma secretase complex aims to better understand its structure-function relationship and regulatory mechanisms. Advances in
cryo-electron microscopy have provided detailed insights into the complex's structure, which could aid in the design of more selective inhibitors or modulators. Moreover, further elucidation of gamma secretase's role in various diseases beyond Alzheimer's, such as cancer, could open new avenues for therapeutic development.
