Neuropathology of the NGF Receptor System in Alzheimer's Disease

         ?During the past several years scientific evidence has been accumulating that the loss of mental abilities in Alzheimer’s disease (AD) may result from a deficit in brain systems which are under the influence of growth factors . Perhaps the most widely studies of these substances is nerve growth factor (NGF). It was originally thought that NGF was only essential for the development and maintenance of structures located within the peripheral nervous system. However, recent studies indicate that NGF participates in the survival of a group of cell bodies located deep within the brain in a region known as the basal forebrain which is consistently damaged in AD. It is now well established that the effects of NGF are mediated by the interaction with specific receptors present on the surface of NGF responsive cells. In fact, interest in NGF has been fueled by the suggestion that treatment with NGF may therapeutically benefit patients with AD.         What is not completely understood is the mechanism(s) which may underlie the ability of NGF to promote functional recovery in AD patients. Several lines of research indicate multiple processes may underlie the action of NGF including transitory expression of NGF receptor and concomitant accumulation of NGF, reexpression of NGF / NGF receptor system following brain damage and self repairing processes activated by the release of NGF. However, the response of NGF / NGFR systems to degenerative disease within the human brain remains a m ystery . Our on going investigations of the neuropathologic alterations associated with the NGF / NGF receptor system in AD which is presently supported by AHAF has led to the striking finding that a select population cell bodies within the cortex (outer covering of the brain) express the receptor for NGF in extremely old and AD braJns. Since the cortex is severely impacted in AD and is intimately involved in the execution of mental function, these findings suggest that NGF may be turned on in this disease as well as in advanced aging in an attempt to rescue dying or diseased cortical brian cells. It is the purpose of this application to investigate in great detail these seminal and potentially important findings. Information gathered from this application may shed some new light on possible mechanisms of NGF function within the human brain and thus provide valuable new direction for the pharmacological use of NGF in the treatment of AD and normal aging. The specific aims of this continuation proposal are listed below: 1. We will determine the distribution of NGF receptor containing cell bodies in the     cortex of both AD and normal aged brains, whether these cells express the gene     message for NGFR and what types of cortical cells express the receptor for NGF     using modern cell staining and biochemical techniques. 2. We will substantiate our qualitative observations that in AD as compared to normal     aged brain that there is an increased number of NGFR containing cortical cells     using a rigorous quantitative evaluation. We will test the hypothesis that those     areas most severely impacted with AD type pathology exhibit greater numbers of     NGFR containing cells, that in AD these cells over express the gene message for     NGFR and whether cortical cells express the receptor for NGF in other     neurodegenerative disease (e.g ., Pick’s, Parkinson’s and Parkinson’s with AD) . 3. We will test the hypothesis that Alzheimer’s-like pathological neuronal alterations     suggestive of cellular disfunction are located within these NGFR containing cortical     cells in AD, normal aged or both groups using modern dual brain cell marking     methods.     The proposed studies will expand our on going investigation of the neuropathological alterations seen in NGF receptor systems in AD. The long term goal of our research is to gain a better understanding of the involvement of nerve growth factor and more specifically systems expressing the receptor for NGF in aged individuals and patients afflicted with AD. The dramatic finding that cortical neurons express the receptor for NGF strongly suggests that the human brain may be attempting to heal itse lf during periods of age or disease related stress . Thus, the information derived from the proposed s tudies may indicate that NGF not only may be important for neuronal survival in AD but that this trophic substance may be beneficial as a treatment for retarding the consequences of normal brain aging.