Research Project
9356455
Approximately 5.2 million Americans are affected by Alzheimer?s disease (AD), and up to 13 million will be affected by 2050. At present, there is no preventive or curative treatment for AD or in age-related cognitive decline and clinical trials of cognitive-modifying compounds have not succeeded in identifying an effective treatment. Despite a lot of efforts, no candidates are available to slow down the development or even cure this devastating disease. Although most of the efforts are focusing on the amyloid and the tau pathways, we have taken a different approach and targeted oxidative stress. Oxidative stress is a major pathogenic mechanism that underlies both the pre-clinical development and subsequent progression of AD, and one that could potentially be targeted preventively as well as therapeutically. Levels of reactive oxygen species (ROS) increase during inflammation, mitochondrial dysfunction, and metal redox cycling catalyzed by A?, all processes associated with AD development. ROS-catalyzed lipid peroxidation generates bifunctional electrophiles (BFEs). We have shown that BFEs generated by oxidative stress accelerate Aß oligomerization, generating oligomers that have similar neurotoxicity and immunoreactivity as the amyloid-derived diffusible ligands. They inhibit proteosomal activity, cause mitochondrial dysfunction, and promote dendritic cell activation of T cells. Importantly, we have shown that levels of BFE adducts on proteins are significantly elevated in hippocampus of AD post mortem human brains, and correlate positively with both the CERAD plaque score and the Braak stage. We have found that 2-hydroxybenzylamine (2-HOBA) reacts 1,600-fold faster with BFEs than lysine, preventing protein modification in vitro and in vivo. Importantly, in hApoE4 transgenic mice, 2-HOBA inhibits all the effects of BFEs described above, and prevents working memory deficit. 2-HOBA, a natural product present in buckwheat seeds, has been developed for use in humans by Metabolic Technologies, Inc. (MTI, Ames, IA). The chemical, manufacturing and control data have been generated and pre-clinical pharmacology and toxicology data are currently being collected. In this project, we propose to do single and multiple escalation dose studies necessary to characterize pharmacokinetics, metabolism, and safety of 2-HOBA. We also propose to establish brain penetrance of 2-HOBA and to determine whether it reduces blood and CSF markers of oxidative modification of proteins.
