The overall objective of this proposal is to gain a more complete understanding of the pathologic alterations which occur between galanin containing interneurons and their processes within the cholinergic basal forebrain in Alzheimer's (AD). This relationship needs to be examined in human material, and cannot be accurately modeled in nonhumans, since we have previously demonstrated a dramatic species difference in the cellular distribution of galanin-containing profiles in basal forebrain of monkeys and humans. Since galanin is inhibitory to acetylcholine, it has been hypothesized that hyperinnervation by galanin containing neurites upon nucleus basalis cholinergic neurons in AD may play a key role in the degenerative process(es) underlying cholinergic cell dysfunction in this disorder. To further characterize the relationship between galanin and the cholinergic basal forebrain in AD, we will determine 1) whether the reported hyperinnervation by galanin of nucleus basalis neurons also occurs in the septal/diagonal band complex of the basal forebrain in AD; 2) whether there is an increase in galanin-containing synapses upon cholinergic basal forebrain neurons in AD; 3) whether the embryonic development of galanin-containing basal forebrain efferents is similar to that seen in AD; 4) whether the enhanced galanin-containing input upon cholinergic basal forebrain neurons in AD is due to an increased number of cells expressing galanin mRNA or whether there is an increase in the amount of galanin mRNA being produced in a stable number of neurons. The planned studies will utilize immunohistochemistry using a polyclonal galanin antibody, galanin mRNA in situ hybridization, and immunoelectron microscopy. The data generated from this proposal will provide much needed information concerning the neurodegenerative events which may play a pivotal role in basal forebrain cholinergic degeneration in AD. Furthermore, these data my suggest avenues for the development of new pharmacological therapies as a means of retarding intellectual deterioration in dementia.

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National Institute on Aging (NIA)
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Special Emphasis Panel (SRC (33))
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Rush University Medical Center
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