The Alpha7-Beta2 Nicotinic Receptor and Its Roles in Amyloid Beta Pathology in Alzheimer's Disease

摘要

Accumulation of beta amyloid peptide, including A??1-42, is a hallmark of Alzheimer's disease (AD). In the early stages of AD, neuronal death is observed in the septum and the hippocampus of the brain. This neuronal death causes memory and cognitive dysfunction which are clinical manifestations of AD. A newly-discovered neurotransmitter receptor subtype, the a7??2 nicotinic acetylcholine receptor (a7??2-nAChR) is expressed in the septum and the hippocampus of the rodent and human brain. This pentameric receptor has similar functional characteristics to a7-nAChR, a more prevalent subtype. It has been shown that a7-nAChRs mediate internalization of A??1-42. Others have shown that A??1-42 internalization may cause neuronal dysfunction and death. The aims of the present study are to determine if a7??2-nAChR mediates internalization of A??1-42, if this is toxic to the cells, and if it affects intracellular calcium activity. We have used multiphoton microscopy to show internalization of the peptide in SH-EP1 cells expressing a7??2-nAChR and a7-nAChR, and live/dead assays for measuring cell death. Epi-fluorescence microscopy and calcium dyes are being used to compare calcium activity of cells expressing these receptors. These are preliminary steps toward determining the pathogenic molecular mechanisms of neuronal dysfunction and cell death in early stages of AD.