Evaluating the Combined Neurotoxicity of Amyloid Beta and Tau Oligomers in Alzheimer's Disease: A Novel Cellular-Level Criterion.

Abstract

A criterion characterizing the combined neurotoxicity of amyloid beta and tau oligomers is suggested. A mathematical model that makes it possible to calculate a value of this criterion during senile plaque and NFT formation is proposed. Computations show that for physiologically relevant parameter values, the value of the criterion increases approximately linearly as time increases. Once the formation of neurofibrillary tangles starts in addition to the senile plaque formation, the slope characterizing the rate at which the criterion increases becomes larger. The critical value of the criterion upon reaching which the neuron dies is estimated. Computations predict that unless the production rates of amyloid beta and tau monomers are very large, in order for the accumulated toxicity to reach the critical value, the degradation machinery responsible for the degradation of amyloid beta and tau must become dysfunctional. The value of the criterion after 20 years of the aggregation process is strongly influenced by deposition rates of amyloid beta and tau oligomers into senile plaques and NFTs. This suggests that deposition of amyloid beta and tau oligomers into senile plaques and NFTs may reduce accumulated toxicity by sequestering more toxic oligomeric species into less toxic insoluble aggregates.