Learning and memory impairments occurring with Alzheimer's disease (AD) are associated with degeneration of the basal forebrain cholinergic neurons (BFCNs). BFCNs extend their axons to the hippocampus where they bind nerve growth factor (NGF) which is retrogradely transported to the cell body. While NGF is necessary for BFCN survival and function via binding to the high-affinity receptor TrkA, its uncleaved precursor, pro-NGF has been proposed to induce neurodegeneration via binding to the p75NTR and its coreceptor sortilin. Basal forebrain TrkA and NGF are downregulated with aging while pro-NGF is increased. Given these data, the focus of this paper was to determine a mechanism for how pro-NGF accumulation may induce BFCN degeneration. Twenty-four hours after a single injection of pro-NGF into hippocampus, we found increased hippocampal p75NTR levels, decreased hippocampal TrkA levels, and cholinergic degeneration. The data suggest that the increase in p75NTR with AD may be mediated by elevated pro-NGF levels as a result of decreased cleavage, and that pro-NGF may be partially responsible for age-related degenerative changes observed in the basal forebrain. This paper is the first in vivo evidence that pro-NGF can affect BFCNs and may do so by regulating expression of p75NTR neurotrophin receptors. 1. Introduction Understanding the role of pro-nerve growth factor (pro-NGF) as an independent ligand is an important part of determining a mechanism for degeneration of the basal forebrain cholinergic neurons (BFCNs). BFCNs degenerate in Alzheimer’s disease (AD) and Down syndrome (DS), and this phenomenon is believed to explain some of the cognitive deficits observed in both conditions [1]. In the United States alone, 5.3 million Americans of all ages have AD with one in eight people over the age of 65 diagnosed with AD (Alzheimer’s Association, 2010). The hallmark of AD is progressive cognitive decline, defined by, but not limited to: profound memory loss, difficulty with planning and problem solving, visuospatial deficits, and difficulty with word use in speaking or writing (Alzheimer’s Association, 2010). Ultimately, the progressive culmination of these symptoms leads to a loss of independent living. Current drug therapies for AD target the cholinergic system by increasing the amount of available acetylcholine without protecting cholinergic neurons from further degeneration and have been only mildly successful in slowing the progression of cognitive impairment in the clinic [2]. Because BFCN integrity is correlated with cognitive function, it would be
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