Oct 11, 2013

Substrate ectodomain is critical for substrate preference and inhibition of γ-secretase

Nature Communications
Satoru FunamotoYasuo Ihara


Understanding the substrate recognition mechanism of γ-secretase is a key step for establishing substrate-specific inhibition of amyloid β-protein (Aβ) production. However, it is widely believed that γ-secretase is a promiscuous protease and that its substrate-specific inhibition is elusive. Here we show that γ-secretase distinguishes the ectodomain length of substrates and preferentially captures and cleaves substrates containing a short ectodomain. We also show that a subset of peptides containing the CDCYCxxxxCxCxSC motif binds to the amino terminus of C99 and inhibits Aβ production in a substrate-specific manner. Interestingly, these peptides suppress β-secretase-dependent cleavage of APP, but not that of sialyltransferase 1. Most importantly, intraperitoneal administration of peptides into mice results in a significant reduction in cerebral Aβ levels. This report provides direct evidence of the substrate preference of γ-secretase and its mechanism. Our results demonstrate that the ectodomain of C99 is a potent target for substrate-specific anti-Aβ therapeutics to combat Alzheimer's disease.

Mentioned in this Paper

Familial Alzheimer Disease (FAD)
HEK293 Cells
APP protein, human
Leukocyte Differentiation Antigens, Human
Proteins, Recombinant DNA
Chinese Hamster Ovary Cell
Cytokinesis of the Fertilized Ovum

Related Feeds

Alzheimer's Disease: Abeta

Alzheimer's disease (AD) is a chronic neurodegenerative disease associated with accumulation of amyloid plaques, which are comprised of amyloid beta. Here is the latest research in this field.

Alzheimer's Disease: Transcription

Transcription involves copying (transcribing) the gene's DNA sequence into RNA. Impaired transcription is associated with the pathogenesis and progression of conditions such as Alzheimer's disease (AD). Here are the latest discoveries pertaining to transcription and this disease.

Alzheimer's Disease: APP

Amyloid precursor protein proteolysis is critical for the development of Alzheimer's disease, a neurodegenerative disease associated with accumulation of amyloid plaques. Here is the latest research.