Alzheimer's Disease (AD) is a degenerative 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 and suggest that plaque-associated reactive microglia chronically release cytotoxic factors that contribute to the neuronal injury and synaptic loss resulting in AD dementia. They have identified and characterized neurotoxic activities, produced by microglia when brought into contact with isolated plaques. The same active principles can be extracted from autopsied AD brain. Isolated neurotoxic compounds, lipophilic amines, have been purified over 100,000 fold, show high potency and demonstrate in vivo effects in rat hippocampus. The investigators propose to elucidate the chemical structure of microglia-derived neurotoxins by mass spectrometric and biological studies. They will conduct studies to follow levels of neurotoxins in brain and cerebrospinal fluid. In addition, they will evaluate populations of neurons to determine patterns of vulnerability to microglia-derived neurotoxins. If successful, this proposed research will uncover fundamentally important events that regulate immune-mediated injury to AD brain. Elucidating neurotoxin structures will spur the development of new strategies to treat AD dementia.
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