The investigator is a board-certified neuropathologist who, from 1990-1998, has undertaken full-time clinical residency training and subsequent clinical faculty positions in neuropathology. He was recruited to Northwestern University School of Medicine in 1997 in conjunction with the new Alzheimer Disease Core Center (NIA-ADCC), under Dr. M.-Marsel Mesulam, and to develop an independent research laboratory in glial cell biology. Northwestern University provides an excellent environment for Alzheimer's disease research. In addition to the ADCC and an established clinical-basic neuroscience umbrella institute, there are leadership figures in tau neurochemistry (Dr. L. Binder), glial biology in AD (Dr. Van Eldik), and amyloid neurotoxicology (Drs. Klein and Krafft). Graduate coursework in cell and molecular biology and formal Alzheimer or Geriatrics seminar series all contribute to the K08 training opportunities. The goal of this clinician training grant is to fully train the investigator in cell culture investigation models of glial-neuronal pathobiology in Alzheimer's disease and efficiently prepare him for independent NIH-funded research in this field. This training program is entirely new and will dramatically increase Dr. Quinn's basic science research capabilities, while the proposed program builds on his professional clinical training credentials and commitment to human neuropathology and experience with human disease neuroanatomy. The sequence of cellular and intercellular mechanisms underlying brain deterioration in Alzheimer's disease remains controversial, so that entry points and arrest targets remain uncertain. It is established that different parts of the neocortex have either markedly different vulnerability to AD pathobiology or rate- inhibition of AD progression, while immune-related, oxidation- related (tocopherol) or glial-related (propentofyline) drugs all may be able to impact on global neurobehavioral disease progression. While local glial contributions to disease progression are actively under study, the cause of very marked differences in astrocytic reactivity to amyloid in different brain areas (both in autopsy material and in vitro) remains unknown. The proposed studies aim to elucidate the cellular basis of cortical versus cerebellar astrocyte vulnerability or resistance to beta-amyloid toxicity, using different forms of beta-amyloid and utilizing molecular assays of entry points which trigger cytokine responses and nitric oxide production only in certain astrocyte types. These results will be validated using established techniques for rapid human postmortem glial culture in collaborating laboratories. In vitro differential study of neocortical and non-neocortical astrocytes in these model systems will facilitate the targeting of future interventions in the cascade of in vivo Alzheimer pathobiology.
