This grant addresses estrogen ability to regulate trophic support for forebrain cholinergic circuits known to be at risk in Alzheimer's disease. Cholinergic neurons in the diagonal band of Broca (nDBB) project to, and obtain trophic support from, neurons in the olfactory bulb. Trophic support for cholinergic neurons is provided by a family of growth factor peptides called the neurotrophins and the proposed experiment will test whether estrogen regulates cholinergic function by modulating the availability of neurotrophins. These experiments are based on the hypothesis that reduced trophic support to hormone-sensitive cholinergic neurons resulting from an age- or disease-related decline in estrogen may contribute to the risk of Alzheimer's disease. Experiments in Specific Aim I will test whether estrogen can restore cholinergic function in neurons deprived of olfactory bulb-derived neurotrophins: An in vivo paradigm consisting of intact, ovariectomized and estrogen-replaced animals will be used to assess estrogen's neuroprotective effects on basal forebrain cholinergic neurons following the destruction of bulbar cells by excitotoxic lesion. These studies will also test whether estrogen can, in a lesioned model, stimulate neurotrophin-mediated adaptive responses in other forebrain targets of the septum-diagonal band cholinergic neurons. Experiments in Specific Aim II will examine whether estrogen regulates the ability of cholinergic neurons to bind and transport target-derived growth factors from the olfactory bulb. Using a similar paradigm (intact, ovariectomized, estrogen replaced-ovariectomized animals), these experiments will test whether estrogen modulates the expression of p75, (the pan-neurotrophin receptor) as well as trkA and trkB (the specific tyrosine kinase receptors for NGF and BDNF) in basal forebrain neurons. Furthermore, these experiments will test whether estrogen replacement stimulates receptor mediated transport of neurotrophins from the bulb. Due to its proximity and connections with the nasal mucosa, bulb neurons are especially vulnerable to environmental toxins and viruses, as are its efferent fibers that obtain trophic support from the bulb. Factors that regulate trophic support for cholinergic afferents during injury may significantly impact on the etiology and clinical management of forebrain neurodegenerative diseases. Molecular actions of estrogen on the forebrain are particularly relevant in view of the recent retrospective studies and small-scale clinical trials which suggest that estrogen replacement therapy (ERT) may be beneficial for the management of Alzheimer's disease.
