GALANIN REMODELING IN THE PROGRESSION OF ALZHEIMER'S DISEASE

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Recently, a consensus has been generated linking the neuropeptide, galanin to cholinergic basal forebrain function in normal and pathologic states including AD. Numerous experimental studies have shown that galanin inhibits acetylcholine (ACh) levels in vitro and impairs working memory in rats, we and others have shown that galaninergic systems undergoes a hyperplastic response upon remaining CBF neurons which may alter ACh neurotransmission. Cholinergic deficits in AD occur early in the disease process and correlate with both the severity and duration of this disorder. Moreover, a vast animal and clinical literature connects CBF neurons, which innervate the cortex and hippocampus; to memory function. We have demonstrated a dramatic species difference in the molecular signature of GAL-innervation within the CBF between humans and experimental animals including monkeys. These observations indicate that animal models of GAL- based CBF interactions do not accurately mimic the human condition. Thus, only investigations examining the human GAL/CBF system may truly be relevant towards elucidating the mechanisms (s) underlying the interaction between GAL and ACh within athe CBF. Thus, studies of the GAL/ACh interaction within the human CBF will provide a greater understanding of the pathologic process(es) affecting cholinergic cell dysfunction in AD. The purpose of this subproject is to investigate the pathophysiologic changes underlying galanin plasticity within the CBF and their relation to the progression of cognitive decline in AD. We will test the hypothesis that GAL remodeling is associated with an increase in the number of GAL mRNA-expressing neurons in AD. Alternatively, we will test the hypothesis that there is an increase in GAL mRNA synthesis per neuron within the CBF in AD. We will determine whether galanin hypertrophy is associated with an increase ina the number of receptor sites (Bmax) or a change in GAL affinity (binding; KD) within the CBF in AD. We will also test the hypothesis that there is a regional specificity of changes in GAL receptor binding within the CBF in AD. These studies will use neuropsychological testing, radioimmunoassay, in situ hybridization and receptor pharmacology procedures. The data generated from these studies will provide new information concerning the unique galanin basal forebrain remodeling response as a function of disease progression. Furthermore, these data may suggest avenues for pharmacological therapies aimed at retarding intellectual deterioration in AD.