Alzheimer's disease neuropathology is characterised by b-amyloid plaques and neurofibrillary tangles. Inhibition of b-amyloid accumulation may be essential for effective therapy in Alzheimer's disease. In this study we have treated transgenic mice carrying the Swedish mutation of human amyloid precursor protein [Tg(Hu.APP695.K670N-M671L)2576], which develop brain b-amyloid deposits, with nicotine in drinking fluid (200 lg/mL) from 9-14.5 months of age (5.5 months). A significant reduction in amyloid b peptide 1-42 positive plaques by more than 80% (p < 0.03) was observed in the brains of nicotine treated compared to sucrose treated transgenic mice. In addition, there was a selective reduction in extractable amyloid b peptides in nicotine treated mice; cortical insoluble 1-40 and 1-42 peptide levels were lower by 48 and 60%, respectively (p < 0.005), whilst there was no significant change in soluble 1-40 or 1-42 levels. The expression of glial fibrillary acidic protein was not affected by nicotine treatment. These results indicate that nicotine may effectively reduce amyloid b peptide aggregation in brain and that nicotinic drug treatment may be a novel protective therapy in Alzheimer's disease.

No abstract

Ten days treatment with nicotine reduced insoluble amyloid A beta 1-40 and Alpha beta 1-42 peptides by 80% in the cortex of 9-month-old APPsw mice, which is more than that observed in 14.5-month-old mice following nicotine treatment for 5.5 months. A reduction in A beta associated with cerebral vessels was observed in addition to that deposited as parenchymal plaques after 5.5 months treatment. The diminution in A beta peptides observed was not accompanied by changes in brain alpha, beta or gamma secretase-like activities, NGF or BDNF protein expression measured in brain homogenates. A significant increase in sAPP was observed after nicotine treatment of SH-SY5Yneuroblastoma cells that could be blocked by the nicotinic antagonist mecamylamine. Attenuation of elevated [(125)I]-alpha bungarotoxin binding (alpha 7) in APPsw mice was observed after 5.5 months nicotine treatment. Both these observations suggest that the reduction in insoluble A beta by nicotine might be in part mediated via the alpha 7 nicotinic receptor. Further studies are required to identify potential mechanisms of the nicotine's amyloid-reducing effect.

Neuronal nicotinic receptor binding sites as well as mRNA levels encoding for subunits alpha4, beta2, and alpha7 were analysed in 3-mo-old transgenic mice generated with a neuronal overexpression of human acetylcholinesterase and in age-matched controls. The acetylcholinesterase transgenic mice display progressive cognitive impairment in spatial learning and memory. We here report a significantly increased [3H]epibatidine and [125I]alphabungarotoxin binding in the cortex and the caudate putamen of these mice. Quantitativein situ hybridization showed significant upregulation of mRNA corresponding to the nicotinic receptor subunits alpha4, beta2, and alpha7 in various brain regions in the transgenic mice compared to nontransgenic controls. Our results suggest that disruption of balanced cholinergic transmission by constitutive overexpression of acetylcholinesterase is accompanied by variable upregulation of several nicotinic receptor subtypes, in particular these associated with cholinergic terminals participating in compensatory response.