Alzheimer's Disease (AD) is a degenerative disorder associated with senile plaques. Although loss of cortical neurons, decreased synaptic connection, and marked reactive microgliosis are prominent features of AD, the mechanisms to account for these histologic abnormalities remain uncertain. The applicant believes that AD plaques elicit local microglial reactivity. Because of their size and chemical stability, these plaques, containing a complex of collection of constitutes including beta amyloid, persist as chronic irritants. The applicant's suggest that plaque-associated reactive microglia chronically release cytotoxic factors that contribute to the neuronal injury and synaptic loss resulting in AD dementia. The applicant's 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 demonstrated in vivo effects in animal brain. The applicants propose to elucidate the chemical structure of this toxin by mass spectrometric and NMR studies. In addition, they will conduct studies to understand the mechanisms by which beta-amyloid, the major constitute of plaques, elicit the adherence and neurotoxicity of microglia. They will also evaluate the roles of minor protein constituents of native senile plaques in these behaviors. Finally, they have also produced an animal model for the role of microglial neurotoxicity on AD, through direct infusion, of the toxin into rat hippocampus. The investigators will conduct in vivo investigations to evaluate a number of candidate NMDA receptor blocking agents for effect in preventing the neuronal death which results from this neurotoxin in the brain. If successful, this proposed research will uncover fundamentally important signals and events which regulate immune-mediated mechanisms of brain injury in AD. Uncovering such mechanisms may lead to the development of immunosuppressive strategies to treat AD dementia.
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