Brain damage found in patients with alzheimer's Disease is associated with loss of cortical neurons, decreased synaptic connections, and clusters of reactive microglia. As principal immune cells of the brain, microglia are thought to mediate immunopathology of AD. Although the mechanisms to account for neuronal damage remains uncertain, a growing body of evidence suggests that the reactive microglia contribute to neuronal death by release of various neurotoxic factors. Recent work has described one of the factors as a lipophilic amine (referred to as NTox) after microglia come into contract with senile plaque. An important and interesting feature of NTox is that it is blocked by n- methyl-D-aspartate (NMDA) receptor antagonists suggesting that its principal action involves the NMDA receptor. To study the action of NTox upon the NMDA receptor, cDNA constructs will be placed into oocytes and into mammalian cell lines in order to measure changes in currents obtained by patch clamp. Cell-killing experiments will explore the properties of the NMDA receptor in expression systems that permit vulnerability to NTox. Splice variants and specific genes of the NMDA receptor will allow a thorough study of the interaction of Ntox with specific domains of the receptor. If successful, the work proposed here will yield fundamental information on mechanisms of immune-mediated destruction of neurons and may offer new strategies for treatment of dementia of aging.
