Nicotine reduces the secretion of Alzheimer's β-amyloid precursor protein containing β-amyloid peptide in the rat without altering synaptic proteins

Alzheimer's disease (AD) is characterized by cerebrovascular deposition of the amyloid P-peptide (Abeta), which is derived from a larger beta-amyloid precursor protein (betaAPP). Altered metabolism of betaAPP, resulting in increased Abeta production, appears central in the neuropathology of AD. The processing of the holoprotein betaAPP by different "secretase" enzymes results in three major carboxyl-truncated species. One species, which results from the cleavage of betaAPP by gamma-secretase, is secreted into the cerebrospinal fluid (CSF) and is called sAPPgamma as it contains an intact Abeta domain. Moreover, AD is characterized by cholinergic dysfunction and the loss of synaptic proteins. Reports of an inverse relation between nicotine intake, due to cigarette smoking, and the incidence of AD prompted us to investigate the effects of nicotine on betaAPP processing and synaptic proteins in rats and in cell culture. Nicotine, 1 and 8 mg/kg/day, doses commensurate with cigarette smoking, and a higher but well tolerated dose, respectively, was administered over 14 days to rats. Levels of sAPP in the CSF sample were evaluated by Western blot analysis. The higher dose significantly increased levels of total sAPP; however, both doses significantly reduced sAPPgamma, which contains the amyloidogenic portion of Abeta. These actions were blocked by nicotinic receptor antagonism. Nicotinic antagonists alone had no effect on either total sAPP or sAPPgamma levels in CSF. Nicotine did not significantly change the intracellular levels of total betaAPP in rat brain extracts, which is consistent with neuronal cell culture data. Similarly, levels of vesicular protein, such as synaptophysin, and presynaptic terminal protein sNAP-25 were unaffected by nicotine treatment both in vivo and in cell culture experiments. Taken together, these results suggest that nicotine modifies betaAPP processing away from the formation of potentially amyloidogenic products, without altering the levels of synaptic proteins, and that this can potentially offer therapeutic potential for Alzheimer's disease.