Oxidative damage and inflammation accumulate as we age and are prominent components of many genetic and age-related diseases. Alzheimer?s Disease (AD), and many other neurodegenerative diseases, show signs of oxidative damage and inflammation early in the disease progression. It is likely that the accumulation of a protein, the ?-amyloid precursor protein and its cleavage products, stimulates oxidation and inflammation in AD, beyond an organism?s ability to properly regulate the normally protective responses. Nrf2, a transcription factor, is part of an organism?s normal mechanism to activate a response to abnormal proteins. It regulates >100 genes that can be protective of oxidation, inflammation, xenobiotic stress, and autophagy. However, in AD, it appears that the activity of Nrf2 is not upregulated in response to the disease process. One approach is thus to augment the body?s natural response by delivering the Nrf2 gene using viral gene therapy. This approach has been successful in prolonging vision in animal models of neurodegeneration and acute nerve damage. We propose to test the ability of Nrf2 to reduce the neuronal death and behavioral symptoms in two mouse models of AD. The viral vector, AAV, that will be used for delivery directly to the brain, is being tested as this vector is emerging as a viable candidate for clinical applications. Two mouse models of AD with different genetic causes of AD will be tested to determine if the strategy is applicable across the disease spectrum. In addition, several different assays will be used to test different types of responses as indicators of efficacy. If effective, AAV-Nrf2 may prove to be useful in extending neuronal health and function, not only in AD, but perhaps in other neurodegenerative diseases that also exhibit inflammation and oxidaiton.
There are several types of age-related neurodenerative diseases that are increasing in frequency as our population ages. These diseases include Alzheimer?s Disease, a devastating disease characterized by loss of learning and memory. Current treatments of Alzheimer?s and other neurodegenerative diseases are not effective, and new modalities are needed. We propose to use viral gene therapy to deliver a gene, Nrf2, to Alzheimer?s brains to augment the body?s ability to combat this disease.
