R. Douglas Shytle, Ph.D.

A Novel Cholinergic Approach to Alzheimer's Disease

Alzheimer's disease (AD) neuropathology is characterized by beta amyloid plaques and neurofibrillary tangles. Therefore inhibition of Abeta accumulation may be essential for effective treatment of the disease. Epidemiological studies suggest that tobacco use is associated with a reduced risk of developing AD. In addition, lower amyloid plaque densities have been observed in autopsy cortical tissue of smokers compared to non-smokers.. These findings are supported by studies demonstrating neuroprotective properties of nicotine in vitro and in vivo studies demonstrating that chronic nicotine effectively reduces Abeta peptide aggregation in the brains of Abeta overproducing mice.

While the mechanism(s) for nicotine's neuroprotective properties are unclear, our lab recently discovered that nicotine (5 µM) and acetylcholine (10 µM) each reduced microglial activation that had been induced by the bacterial endotoxin, lypopolysaccaride (LPS). This reduction in microglial activation is blocked by, a-bungarotoxin, which is an antagonist of the a7 acetylcholinergic nicotinic receptor (nAChR) antagonist. Our findings uncover a potentially important endogenesis anti-inflammatory cholinergic pathway in the brain that regulates microglial activation through a7 nAChR receptors. Negative regulation of microglia activation may represent additional mechanism underlying nicotine's reported neuroprotective properties.

We propose to fully characterize the dose-response functions of galantamine, a weak acetylcholinesterase inhibitor and a potent allosteric potentiating ligand of nAChRs, that is approved and effective for treatment of Alzheimer's disease, as well as nicotine, and their combination on microglial activation in vitro. Based on these data, we then plan to select the optimal synergistic combination dose for in vivo studies assessing the degree of amyloidosis and on cerebral inflammation following chronic galantamine/nicotine treatment in AP overproducing mice. The results from this study will be used to assess the feasibility of designing and conducting a full-scale clinical trial in AD.