Alzheimer's Disease (AD) is a degenerative disorder associated with deposits of plaques containing the protein beta amyloid. Although loss of cortical neurons, decreased synaptic connections, and marked reactive gliosis are prominent features of AD, the mechanisms to account for these histologic abnormalities remain uncertain. We believe that AD plaques are recognized as foreign bodies in the brain and elicit local microglial reactivity. Because of the size and chemical stability, these plaques are difficult to eliminate from CNS tissues and, therefore, persist as chronic irritants. We suggest that plaque-associated reactive microglia chronically release cytotoxic factors that cause cell death and gliosis in surrounding tissues. To investigate the ability of AD plaques to activate microglia, we will carry out quantitative neuropathologic studies of microglial subtypes and plaque classifications from AD brain obtained through autopsy. We will employ in vitro models to extend these observations by measuring plaque and beta amyloid effects upon cultured rat and human microglia. Endpoints will include altered morphology, up regulation of surface receptors, release of cellular modulators, and cytokinetic effects induced by plaques upon cultured microglia. In order to uncover the relationships between microglia and neuronal injury in AD, we will measure plaque-stimulated production of neuron-killing factors in vitro and the production of neuron-killing factors in human brain tissues. We will also explore the ability of plaques to elicit cell- contact injury of neurons. Major and minor protein constituents of amyloid deposits will be isolated by Dr. Alex Roger and used to assess the which components of native plaques drive microglial reactivity. Quantitative measures of neuroanatomic changes in AD brain using confocal scanning laser microscopy will help to elucidate reactive microglia associations with neuronal and synaptic loss. 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 will be necessary in developing rational immunosuppressive strategies for treatment of dementia.
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