The objective of Project One is to address the idea that overexpression of glia-derived cytokines, especially interleukin-1 (IL-1), is a seminal event in the pathogenesis of Alzheimer's disease (AD), giving rise to a two-armed cascade of cellular and molecular events that lead to neuron cell dysfunctions, including accumulation of neurofibrillary tangles and overgrowth of neurites, and eventually death which induces further overexpression of IL-1 in what becomes then a self-propagating """"""""system"""""""" or cascade. In AD, we seek evidence of the involvement of cascade-related cellular and molecular events in the presumed neuropathological progression that accounts for the progressive nature of the dementia by determining their interrelationships with regard to: (i) specific plaque types and (ii) the recognized regional distribution of neuropathological changes in AD. In head injury, a recently established risk factor for later development of AD, we can know the time and age at onset, severity, and clinical course and thus relate these parameters to the distribution of plaques according to type within as well as across brain regions. In non-demented critical coronary artery disease (cCAD) patients where significant AD-like neuropathological changes have been observed, we seek to clarify the relationship of these changes to AD as we: (i) compare their regional distribution to that in AD and (ii) assess the potential involvement of cascade-related cellular and molecular events in specific plaque types within and across brain regions. In refractory temporal epilepsy, where we have evidence that some cascade-related cellular and molecular events occur, we seek to: (i) evaluate spatial relationships between defined epileptogenic foci and these events and (ii) compare these with those occurring in AD, head injury, and cCAD. A number of molecular techniques routine to our laboratory will be used to address our specific aims, which at successful completion will provide information regarding the generalizability of our proposed cascade--a necessity if it is to be useful in developing rational therapeutic strategies.
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