Alzheimer's disease (AD) is a common devastating neurodegenerative disease. As with other chronic neurodegenerative diseases, the pathogenesis remains unknown, even though gene mutations causing familial AD were discovered over 20 years ago. The neuropathology of AD is characterized by extracellular amyloid plaques, comprised primarily of fibrillar Abeta 1-40 and Abeta 1-42 proteins derived from amyloid precursor protein (APP) and intracellular neurofibrillary tangles comprised primarily of tau protein. Abeta protein deposition is promoted by interaction with zinc. Abundant evidence supports the hypothesis that amyloid plaques themselves are not toxic but rather the toxicity is primarily due to the soluble oligomeric Abeta 1-42 fragment of APP (oA?). Several of the mutations that cause AD affect the processing of APP to increase the production of oA?, consistent with the amyloid hypothesis. The eye is part of the central nervous system (CNS), and an extension of the amyloid hypothesis has developed over the last 15 years with the recognition that the retina is affected by the deposition of Abeta in AD, and that Abeta may play a role in retinal diseases involving degeneration of retinal neurons such as glaucoma and age-related macular degeneration. Optic nerve injury (ONI) is another important retinal disorder, and the consequences of transection of axons in the optic nerve is death of retinal ganglion cells and failure of axon regeneration. There has been little or no study of the role of Abeta production and deposition in the neurodegeneration and failure of regeneration following ONI, or how ONI might affect APP processing. In preliminary experiments, using an antibody against Abeta proteins, we have found Abeta aggregates at the site of injury to the optic nerve forming weeks after injury in normal animals but not in animals with a knockout of the zinc transporter ZnT3. We hypothesize that APP processing is highly influenced in the retina by ONI and, that APP processing may play important roles in the neuronal loss and regenerative failure following ONI. To test this hypothesis, we propose the following aims:
Aim 1. Characterize APP expression and Abeta deposition in the normal mouse retina and following ONI.
Aim 2. Assess the effects of altering zinc homeostasis and tetanus toxin on the processing of APP after ONI.
Aim 3. Assess the effect of blocking Abeta production on neuronal survival and regeneration failure after ONI.
TO ALZHEIMER'S DISEASE: Our understanding of the processing of APP is incomplete. The cause of abnormal production of Abeta in sporadic AD is unknown as is the basis for the toxicity of oA? to neurons. APP processing, Abeta production, and Abeta aggregation are influenced by oxidative stress, zinc and copper homeostasis, neuronal activity, axonal transport, and growth state of axons all of which are important in the pathophysiology of ONI. The ONI model offers a uniquely accessible in vivo model of the CNS for the study of APP processing, the factors modulating this processing, and the toxicity of oA?. It is hoped that the work outlined in this proposal will ultimately lead to new approaches for treating AD.