Mechanisms Of Amyloid β-peptide Shedding From Membranes

Alzheimer’s disease(AD)is the most common form of senile dementia characterized by a progressive loss of memory,cognitive impairment,loss of social appropriateness,and decline in capacity to communicate.,its pathological hallmarks include the loss of neurones,as well as the accumulation extracellular amyloid plaques and intracellular neurofibrillary tangles in the brain.Senile plaques are composed of amyloid β-peptide(Aβ),accumulation and aggregation of Aβ to soluble and potentially cytotoxic oligomers,as well as ordered stable amyloid fibres is considered to be the crucial role in the pathological hallmarks of AD.Ap is a 37-43 amino acid peptide that produced by cleavage from the transmembrane protein,amyloid precursor protein(APP),whereby cleavage by BACE1 and y-secretase respectively,and the cleaved peptide will retain membrane affinity.It has been shown that In vitro Aβ is capable of specifically binding to phospholipid membranes with a relatively high affinity,and that modulation of the composition of the membrane can alter both membrane-amyloid interactions and toxicity.In this paper,we use phospholipids that components of biomimetic membrane and Aβ of different lengths to establish a model of phospholipid film combine with Aβ in vitro,to simulate the binding between Aβ and the membrane surfaces.By changing pH in the microenvironment to explore what factors may affect the process of Aβ shedding from biomimetic membrane under physiological conditions.We concluded that Aβ protein’s structure,composition of phospholipid monolayer,pH changes in the microenvironment would have an impact on the Aβ’s release process and would be a key factor in the regulation of Aβ’s release.Under physiological conditions,the lipid rafts domain and acidic conditions would promote the release of Aβ1-42 and Aβ1-40,Aβ17-42 primarily release under neutral conditions and the phospholipid domain.The hydrophobic C-terminal determines the ability of Aβ release,and hydrophilic N-terminal more sensitive to changes in microenvironmental conditions.