Harrison Snyder and Jonathan Wisco, Physiology and Developmental Biology

The Receptor for Advanced Glycation Endproducts (RAGE) is known to have a role in inflammatory processes. When produced in excess it induces oxidative stress by activating a number of ligand enzymes, resulting in the generation of excessive cytosolic reactive oxidant species. This oxidative stress then stimulates Nuclear Factor Kappa-B (NF-kB), which regulates immune response and inflammation. When RAGE is incorrectly regulated, inflammation occurs in otherwise healthy tissue, a process implicated in neurodegenerative disorders like Alzheimer’s disease. RAGE is found throughout the body and is seen in greater concentration in inflamed tissues; it has also been found in the brain tissue of Alzheimer’s disease patients, leading to a potential link between the molecule and the disease.

This study attempts to elucidate the relationship between oxidative stress, the RAGE protein, and the progression of Alzheimer’s disease symptoms. Transgenic mice are the model of choice for the experiments. Wild type, amyloid, tau, and ApoE mice are being bred for the study; the wild type mice serve as controls, while the transgenic mice each display different aspects of Alzheimer’s disease pathology. In some of these mice, oxidative stress is accelerated by treatment with homocysteine or doxorubicin. Antioxidants (clioquinol, metformin or zinc) will be administered to healthy mice, transgenic mice without oxidative stress induction, and transgenic mice with oxidative stress induction. At multiple time points, behavioral data will be collected by utilizing a radial arm maze exercise in order to test the function of their memory. After the death of each mouse, histological data will be collected from brain tissues in an effort to correlate the prevalence of RAGE, Alzheimer’s pathologies, and behavioral changes with the oxidative state of the subject.

The project is still early in its development; thus, no meaningful data has yet been collected. The experiment is designed to take measurements during the lifespan of a transgenic mouse expressing Alzheimer’s disease, meaning that it takes at least six months to collect a full range of data on one subject. In addition, it has taken longer than expected to breed a large enough mouse population from which to collect meaningful data, and the process is complicated by the fact that some of the transgenic species require sterile heterozygous phenotypes in order to properly express the pathology. At the current stage, baseline behavioral data has been collected for most of the test population and the experimental dietary treatments have begun, but there is not yet enough data for meaningful analysis.

The current hypothesis states that RAGE may be involved in the progression of Alzheimer’s disease. Therefore, it is expected that the transgenic mice will perform poorly as compared to the control group in behavioral testing, and that RAGE will be found more prevalently in the brain tissue. Subjects receiving oxidants to induce oxidative stress are likely to perform still worse in behavioral tests with correlated findings in brain histology, while subjects receiving antioxidant rescue treatments are expected to see improved results in behavioral testing when compared to the untreated diseased and oxidative stress groups.

Once the project is complete, data will be analyzed and a report will be published. If we are able to demonstrate a link between antioxidant treatments and the progression of the clinical manifestations of Alzheimer’s disease, the study may have implications for clinical therapies for the disease designed to delay the onset of symptoms. The results of the RAGE studies may provide an explanation for the results of these treatments. We extend thanks to ORCA and to the donors for making this study possible.