Nicotine has been proposed to be neuroprotective through anti-b-amyloid (Ab) effects, anti-excitotoxic effects, anti-free radical effects and amyloid precursor protein (APP) effects. Anti-Aβ effects identified include inhibition of Ab aggregation and reduction of Aβ fibril formation in vitro as well as protection against Ab toxicity. Important in the above listed possible neuroprotective activities of nicotine are the anti-Aβ effects seen in vitro. These results suggest that nicotine could possibly inhibit amyloid deposition in vivo. However, results reported to date on this idea are inconclusive, with studies showing both increases and decreases in Aβ depending on the transgenic mouse model and treatment time. Transgenic mouse (Tg) line J20 overexpressing mutated human APP transgenes (Swedish mutations: K670N and M671L and Indiana mutation: V717F; Mucke, et al., 2000) were used in this study. Nicotine (200 ug/ml) freshly prepared in 2% sucrose in drinking water every three days was given to 15 Tg mice to consume orally starting from 3 months of age for 5 months. A matched group of 15 Tg mice were administered vehicle (2% sucrose in drinking water). Mouse brains were perfused with phosphate buffered saline. One hemisphere was snap frozen for biochemical analysis and receptor binding. Non α-7 nicotinic receptor binding levels were conducted using 3H-epibaditine (3H-EPI). Aβ 1–42 and 1–40 concentrations in hippocampus and cortex were assayed by human Aβ42 and Aβ40 ELISA kits (Biosource). The other hemisphere was fixed in 4% paraformaldehyde for 24 hrs and processed for Aβ immunohistochemistry and thioflavin S histochemistry. Tg mice exposed to nicotine had a significant increase in 3H-EPI binding (59.1±10.3 fm/mg protein) compared to VEH (48.5±9.5, p0.01). However, nicotine treatment from 3 to 8 months of age in J20 APP Tg mice did not lower Aβ 1–42 and 1–40 in hippocampus and cortex compared to VEH. Chronic nicotine treatment does not lead to reduction of Aβ in the J20 Tg mouse model for Alzheimer's disease.
MCI is considered the transitional clinical phase between normal aging and AD. Neurochemical and pathological studies do not consistently show MCI as a transitional phase between normal aging and AD but sample sizes have been limited as relatively few individuals will expire prior to conversion to dementia. To assess the neuropathological and nicotinic receptor binding differences in clinically and pathologically described non–demented controls (NC), mild cognitive impairment (MCI), and Alzheimer's disease (AD). We examined 21 NC, 13 MCI, and 70 AD subjects that were prospectively followed to autopsy. NC subjects had no demonstrable cognitive or functional impairment. MCI subjects clinically met Petersen criteria and expired prior to converting to AD. AD subjects clinically met NINDS–ADRDA criteria for AD. Nicotinic receptor binding was done with [3H] epibatidine. All subjects underwent complete neuropathological analysis for plaque and tangle counts and Braak staging. Subjects with AD were significantly younger, less educated, and more cognitively and globally impaired at last exam before death. When categorized by diagnostic category, MCI was always intermediate between NC and AD clinically. MCI was also pathologically intermediate between NC and AD for total plaque counts, total tangle count and Braak stage. nAChR binding did not differ between NC and MCI but was significantly less in AD. When the sample was divided histopathologically by the CERAD criteria for diagnosis of AD, the clinical characteristics, plaque totals, tangle totals, and Braak stages significantly differed between AD and all other groups. MCI is the transitional state between NC and AD clinically and neuropathologically. NC and MCI do not differ clinically by the presence or absence of significant plaque pathology. nAChRs are lost mainly during the transition from MCI to AD.
Because epidemiologic and in vitro evidence conflict, the authors studied the association between smoking and Alzheimer disease (AD) in 46 never, 47 former, and 15 active smokers with AD followed to autopsy. Disease parameters were examined by smoking status and amount smoked in bivariate tests and in multivariate models controlling for age, sex, education, and APOE status. Smoking status was not associated with cognitive or neuropathologic measures. However, active smokers were significantly younger at death and higher levels of smoking were associated with shorter disease duration.
Research on acetylcholinesterase inhibitors (ChEIs) indicates that long term exposure increases the level of nicotinic acetylcholine receptors (nAChRs) but the effects of donepezil on nAChRs are not well studied. Therefore, we investigated the effect
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