Deficits in cholinergic function have been implicated in the loss of ability to learn and remember which occurs in Alzheimer's Disease and to some extent in normal aging. Several reports have indicated that both muscarinic and nicotinic receptors are affected as a function of aging and in Alzheimer's Disease. Several subtypes of both muscarinic and neuronal nicotinic receptors have been cloned but drugs selective enough to distinguish between the subtypes do not currently exist. Thus, antibodies with selectivity to each of the subtypes of muscarinic nicotinic receptors have been generated utilizing fusion proteins corresponding to the unique portions of each molecule. We propose to utilize these antibodies: 1. To examine the hypothesis that certain subtypes of muscarinic (m1-m5) or neuronal nicotinic receptors are specifically affected in Alzheimer's Disease. 2. To determine the effects of normal aging on the density of each of the subtypes of muscarinic and nicotinic receptors in human brain. 3. To determine the effects of normal aging on the density of the subtypes of muscarinic and nicotinic receptors in rat brain. Additionally, experiments will be conducted using biochemical (cyclic AMP accumulation or phosphoinositide hydrolysis) and physiological assays (prolactin release) to examine the hypothesis that these responses are blunted in aging due to changes in specific receptors. 4. To examine the hypothesis that in aged rats the observed large differences from rat to rat in the ability to learn is mirrored by a loss of a specific subtype(s) of muscarinic or nicotinic cholinergic receptor in the hippocampus or cortex. Thus, as rats age some will perform well on a Morris swim maze and some will perform poorly. In collaboration with Dr. Michela Gallagher at the University of North Carolina, we will examine the density of each subtype of muscarinic and nicotinic receptor in the brains of aged (24-26 mo.) rats which have been tested behaviorally within one week of euthanasia. Preliminary data from Dr. Gallagher's laboratory demonstrate a change in muscarinic receptors from hippocampus of aged rats that show a learning deficit but not from aged rats that do not show a deficit. These experiments should provide important information about the precise aspects of cholinergic receptors affected in aging and in AD and may provide insight into potential therapeutic targets for e.g. Alzheimer's Disease as well as other cognitive disorders.
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