What is the function of gamma-secretase?
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What is the function of gamma-secretase?
gamma-Secretase catalyzes intramembrane proteolysis of various type I membrane proteins, including the amyloid-beta precursor protein and the Notch receptor. Despite its importance in the pathogenesis of Alzheimer’s disease and to normal development, this protease has eluded identification until only very recently.
What is beta and gamma-secretase?
Sequential cleavage by beta-secretase 1 (BACE) and gamma-secretase (γ-secretase) produces the amyloid-beta peptide fragment that aggregates into clumps called amyloid plaques in the brains affected by Alzheimer’s disease.
What is gamma-secretase made of?
γ-secretase is a high molecular weight complex minimally composed of four components: presenilins (PS), nicastrin, anterior pharynx defective 1 (APH-1), and presenilin enhancer 2 (PEN-2).
What activates gamma-secretase?
The formation of Aβ is directly controlled by the γ-secretase complex and its activator, γ-secretase activating protein (GSAP). GSAP derives from a C-terminal fragment of a larger precursor protein via a caspase-3 mediated cleavage. However, the mechanism regulating this process remains unknown.
Where is gamma secretase found?
Function. Gamma secretase is an internal protease that cleaves within the membrane-spanning domain of its substrate proteins, including amyloid precursor protein (APP) and Notch.
How does gamma secretase inhibitor work?
Gamma secretase inhibitors (GSIs) are a class of drugs that gained attention during the past decade in cancer treatment. The use of GSIs for cancers is primarily based on the premise that GSIs act by inhibiting the cleavage of γ-secretase, which result in blocking Notch 1 signaling [272].
Where is gamma secretase located?
Why would a chemical inhibitor of γ secretase be potentially useful for treating Alzheimer’s disease?
Gamma secretase inhibitors (GSIs) have long been investigated for their potential as Alzheimer’s disease (AD) treatments due to their ability to block secretion of amyloid β-peptide, the precursor of amyloid plaques associated with AD.
How can Secretases lead to worsening of Alzheimer’s disease?
Inhibitors of γ-secretase have failed in clinical trials, causing toxicities resulting from blocking the proteolysis of another substrate and cognitive worsening that may be due to elevation of APP substrates.
What secretase inhibitors?
Secretases inhibitors are important agents that inhibit the development of senile plaques. β-secretase (BACE) inhibitors are in lime light for the drug development of AD. BACE initiates the production of Aβ, so its inhibition provides a valid target for the AD.
How do gamma secretase inhibitors work?
