Alzheimer's disease (AD) is a progressive neurodegenerative disease affecting greater that 10% of the population over 65 years of age. A cardinal symptom of the disease is a profound loss of memory. Given the findings that cholinergic neurons projecting to the cerebral cortex and hippocampus are lost in AD, as well as the putative role of acetylcholine neurotransmission in the processes of learning and memory, it was theorized that restoration of a cholinergic influence might have therapeutic benefit. Unfortunately, clinical trials using medications to enhance synaptic availability of acetylcholine and exogenous agonist have reported little to no improvement in memory. A critical assumption is made in this therapeutic strategy, namely that post-synaptic cholinergic muscarinic receptor-mediated signal transduction remains intact. Recent studies demonstrating impairments in M1 receptor-mediated signal transduction in AD have called into question this crucial assumption and suggest that the M1 receptor is functionally uncoupled from its G protein. Pilot data suggests that the uncoupling may be due to an increase in the phosphorylation state of the receptor. The experiments set forth in this proposal will examine the relation of M1 receptor uncoupling to the neuropathology in AD, as well as the spatiotemporal characteristics of the phenomenon. These results may explain the failure of cholinergic drugs and suggest new targets.
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