Amyloid ? Ion Channels in a Membrane Comprising Brain Total Lipid Extracts.

ABSTRACT: Amyloid ? (A?) oligomers are the predominant toxic species in the pathology of Alzheimer's disease. The prevailing mechanism for toxicity by A? oligomers includes ionic homeostasis destabilization in neuronal cells by forming ion channels. These channel structures have been previously studied in model lipid bilayers. In order to gain further insight into the interaction of A? oligomers with natural membrane compositions, we have examined the structures and conductivities of A? oligomers in a membrane composed of brain total lipid extract (BTLE). We utilized two complementary techniques: atomic force microscopy (AFM) and black lipid membrane (BLM) electrical recording. Our results indicate that A?1-42 forms ion channel structures in BTLE membranes, accompanied by a heterogeneous population of ionic current fluctuations. Notably, the observed current events generated by A?1-42 peptides in BTLE membranes possess different characteristics compared to current events generated by the presence of A?1-42 in model membranes comprising a 1:1 mixture of DOPS and POPE lipids. Oligomers of the truncated A? fragment A?17-42 (p3) exhibited similar ion conductivity behavior as A?1-42 in BTLE membranes. However, the observed macroscopic ion flux across the BTLE membranes induced by A?1-42 pores was larger than for p3 pores. Our analysis of structure and conductance of oligomeric A? pores in a natural lipid membrane closely mimics the in vivo cellular environment suggesting that A? pores could potentially accelerate the loss of ionic homeostasis and cellular abnormalities. Hence, these pore structures may serve as a target for drug development and therapeutic strategies for AD treatment.

SUBMITTER: Lee J 

PROVIDER: S-EPMC6197823 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature