This proposal concerns Alzheimer's Disease (AD), a neurodegenerative disorder associated with senile plaques. Although loss of cortical neurons, decreased synaptic connections, and marked reactive microgliosis are prominent features of AD, the mechanisms to account for these histologic abnormalities remain uncertain. The investigators believe that AD plaques elicit local microglial reactivity. Because of their size and chemical stability, these plaques, containing a complex collection of constituents including beta amyloid, are difficult to eliminate from CNS tissues and, therefore, persist as chronic irritants. The investigators suggest that plaque-associated reactive microglia chronically release cytotoxic factors that contribute to the neuronal injury and synaptic loss resulting in AD dementia. These investigators have identified and characterized a neurotoxin, produced by microglia when brought into contact with isolated plaques. This same toxic agent can be extracted from autopsied AD brain gray matter. The neurotoxic agent, a lipophilic amine, has been purified over 100,000 fold, is distinct from known mammalian neurotoxins, is highly potent, acts through the NMDA receptor, and demonstrates in vivo effects in animal brain. The investigators propose to elucidate the chemical structure of this toxin and correlate chemical structure to functional activity. Quantitative measures of neuronal injury will allow investigation of vulnerability of neurons to the toxin in vivo. The investigators propose to analyze the specific sites of the NMDA receptor complex which interacts with the toxin, and explore pharmacological agents that block the action of the neurotoxin. If successful, this proposed research will uncover fundamentally important events which regulate immune-mediated mechanisms of brain injury in AD.
| Miller, S L; Daikhin, Y; Yudkoff, M (1996) Metabolism of N-acetyl-L-aspartate in rat brain. Neurochem Res 21:615-8 |
| Yudkoff, M; Daikhin, Y; Grunstein, L et al. (1996) Astrocyte leucine metabolism: significance of branched-chain amino acid transamination. J Neurochem 66:378-85 |
| Yudkoff, M; Daikhin, Y; Nelson, D et al. (1996) Neuronal metabolism of branched-chain amino acids: flux through the aminotransferase pathway in synaptosomes. J Neurochem 66:2136-45 |
