The longterm objective of this program is to understand the role that nerve growth factor (NGF) and its receptor (NGFR) play in forebrain cell and memory loss associated with aging and Alzheimer's disease (AD). Evidence is compelling for a dysfunction of basal forebrain cholinergic neurons in AD; there is also considerable evidence for a trophic role of endogenous NGF on basal forebrain cholinergic neurons during development and in adulthood. There are two specific aims of the present proposal, which together are designed to test the hypothesis that elevated levels of a truncated form of the NGFR (NGFRt) in urine or CSF correlated with spatial memory decline. (1) We will first confirm and extend our preliminary observations that urine levels of NGFRt in patients with AD are elevated relative to age-matched patients with no cognitive or neurological impairment, and determine if this elevation correlates positively with the degree of memory dysfunction. (2) To address the mechanism underlying the elevation of NGFRt in urine, we will study in rats the relationship of NGFRt to aging and spatial memory impairment and to basal forebrain neuron degeneration. We will accomplish this (a) by measuring NGFRt levels in urine and CSF of aged rats with poor spatial memory (water maze) ability in relation to a subpopulation of unimpaired-aged or young adult rats, and (b) by measuring the time course of changes in NGFRt levels associated with basal forebrain cell degeneration following axotomy or ibotenic acid lesions. These studies of changes in urine levels of NGFRt should lead to a better understanding of neurobiological basis of cognitive deficits associated with AD. In addition, the measurement of NGFRt in urine could be used as a simple, noninvasive method for diagnosing this disease.
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