Relating molecular mechanisms between cholinergic receptor deficit, changed cellular membrane structure and oxidative stress in Alzheimer¿s disease

The deficit of neuronal nicotinic acetylcholine receptor (nAChRs), changed cellular membrane lipids and oxidative stress have been confirmed to be connected with Alzheimer¿s disease (AD). However, the underlying mechanisms of these changes remained elusive. Specially, the certain functional relationship between modification of the structure lipids and the changes of the receptor proteins in cellular membrane in AD pathogenesis is still unclear. Our previous studies have shown that the decreased number of nAChRs in AD occurs in the levels of receptor binding and subunit protein and that the decreases of phospholipids and their polyunsaturated fatty acids are associated with the pathology of AD. We also found that lipid peroxidation can inhibit the expression of nAChRs at different levels, which provides a clue for the connection of the influence of membrane lipids on the function or synthesis of the protein receptor located in membrane. Recently, our new data have indicated that lipid peroxidation induced directly by amyloid peptides (Abs) might be involved in the mechanism of nAChR deficit. The decreases of nAChR binding sites and the receptor subunit proteins, as well as decrease of membrane neutral lipid resulted from Abs were mostly prevented by the pretreatment with antioxidant. These findings suggest that lipid peroxidation stimulated by Abs might be a reason for the losses of nAChRs associated with the pathogenesis of AD.
This project is based on the results obtained recently by us and we will continually investigate the underlying mechanisms of the deficit of nAChRs, changed membrane lipids and oxidative stress in AD and their relationships in AD pathogenesis. The results obtained from this study will give out the underlying molecular mechanisms in the pathogenesis of AD and develop efficient neuroprotective strategies in the treatment of AD.