Denied Access of Ions and Molecules to Axons in the Development of Alzheimer's Disease

Abstract

Self-assembly of amyloid-beta peptide and the formation of fibers and plaques in extracellular space of the brain is a characteristic of Alzheimer's disease. Whether and how fibers and plaques cause neurodegeneration remains unclear. Recently, we reported that amyloid fibers can further aggregate and form gels. Gels are known to eliminate bulk flow which is required for the circulation of ions and molecules essential for neuronal function. To understand how restriction of ions or molecules affects neurons, we examined the gels’ role in the propagation of nerve fibers’ action potential. Unlike amyloid fibers, fibrin, which forms gels fast, within a couple of minutes, was used to simulate amyloid fiber gels. We found a 40% reduction of the compound action potential when fibrin gel was formed outside frog sciatic nerve fiber epineuriums, a porous membrane wrapping around axon bundles. A 70% reduction of the action potential was recorded when fibrin was formed inside the epineurium. Fibrin encapsulating individual axons was verified under a confocal microscope when fluorescein-labeled fibrinogen was injected. Gelation also changes viscosity, which affects the diffusion of ions and molecules. An approximate 1.42-fold increase of microviscosity during fibrin gelation was revealed using a molecular rotor. Glycerol caused a concentration dependent reduction of the compound action potential. These results imply that the formation of amyloid plaques surrounding neuronal processes initially disrupt the propagation of action potential and then trigger the cascade of events leading to neuronal death seen in Alzheimer's disease. Denied access of the neurites to nutrients, signaling molecules, and/or waste drainage pathways might be responsible for the plaque's effect on the action potential and underlie the pathogenesis of Alzheimer's disease. The methods introduced in the paper for the study of gelation's effect on action potential may have broad applications.