Mechanisms Of Amyloid β-peptide Shedding From Membranes

Alzheimer Disease (AD) is the most common cause of senile dementia. Amyloid beta peptide (Aβ) with a length of 39-42 residues plays a fundamental role in the pathogenesis of AD. Aβ is produced by sequential enzymatic processing of the precursor protein APP, a type I membrane protein. It has been well established that secreted Aβ is neurotoxic and forms extracellular deposits that characterize AD, however, as part of the transmembrane segment of APP, it is less clear that how Aβ is released from membranes after its production. Herein, we have developed a model membrane system for investigating the membrane shedding behavior of Aβ. The results indicate that the shedding of Aβ is regulated by specific lipids, microenvironment conditions and the length of hydrophobic segment. These result suggest that targeted processing in lipid raft microdomains and rapid endocytosis are essential for efficient Aβ shedding.