O5‐03‐03: Epps Reverses Amyloid‐B Aggregation and Ameliorates Hippocampus‐Dependent Cognitive Deficits in APP/PS1 Mice

Alzheimer disease (AD) is characterized by the transition of amyloid-β (Aβ) monomer into toxic oligomers and plaques. Inhibiting the formation of Aβ or Aβ aggregates has been suggested as potential therapeutic approaches for AD. However, given that Aβ aggregation and plaque deposition typically precedes the development of clinical symptoms, an agent additionally capable of disaggregating existing Aβ aggregates might have advantages. Aβ aggregation was monitored using the ThT assay, TEM and SDS-PAGE. MTT assays were performed using HT-22 cell line. SPR analysis was performed using Biacore . 4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid (EPPS) in drinking water was freely administered to 10.5-month-old APP/PS1 transgenic (male) mice, with severe AD-like behaviors and plaque deposits in brains, for 3.5 months with 10 or 30 mg/kg/day dosages. Y-maze tests, fear conditioning tests and Morris water-maze tests are used to evaluate learning/memory of mice. After the behavioral studies, Aβ plaques and inflammation-related proteins were stained. Brain lysates was used in Aβ42- ELISA, western blots and dot blots for biochemical changes and soluble Aβ analyses, respectively. EPPS markedly disaggregated both toxic oligomers and fibrils and prevents Aβ-induced cell damage by direct binding to Aβ aggregates. EPPS significantly rescued memory-related behavioral deficits when orally administered to aged, symptomatic AD model mice in Y-maze, fear-conditioning and Morris water maze tests. EPPS treatment reduced Aβ plaques in transgenic mice in a dose-dependent fashion and substantially eliminated Aβ plaques in the hippocampus at the dose of 30 mg/kg/day (EC50 = 5.22 mg/kg/day). EPPS dose-dependently decreased the amount of oligomeric species, but the concentration of total soluble Aβ, including monomers, was not changed. EPPS treatment markedly reduced levels of astrocytosis, microgliosis and JNK phosphorylation to the level of wild type.