Effect of subchronic treatment of memantine, galantamine, and nicotine in the brain of Tg2576 (APPswe) transgenic mice.

An increasing number of studies suggest that the present clinical therapy used in Alzheimer's disease (AD), in addition to having a symptomatic effect, also may interact with the ongoing neuropathological processes in the brain. The aim of this study was to investigate the effect of the cholinesterase inhibitor galantamine and the N-methyl-d-aspartate (NMDA) antagonist memantine in comparison to nicotine on the neuropathology of Tg2576 transgenic mice (APPswe). Nontransgenic and APPswe mice at 10 months of age were treated subcutaneously with saline, memantine, galantamine, or nicotine for 10 days. Nicotine reduced the guanidinium-soluble amyloid-beta peptide (Abeta) levels by 46 to 66%, whereas the intracellular Abeta levels remained unchanged. Treatment with nicotine also resulted in less glial fibrillary acidic protein immunoreactive astrocytes around the plaques, increased levels of synaptophysin, and increased number of alpha7 nicotinic acetylcholine receptors (nAChRs) in the cortex of APPswe transgenic mice. Galantamine treatment caused an increase in the cortical levels of synaptophysin in the APPswe mice. Memantine treatment reduced the total cortical levels of membrane-bound amyloid precursor protein (45-55%) in both transgenic and nontransgenic mice, which eventually may decrease the level of Abeta. In conclusion, galantamine, memantine, and nicotine have different interactions with Abeta processes, alpha7 nAChRs, and NMDA receptors in APPswe mice. These different effects might have therapeutic relevance, and this knowledge might be applicable to the development of new effective therapeutic strategies for AD.

Early changes in Abeta levels in the brain of APPswe transgenic mice--implication on synaptic density, alpha7 neuronal nicotinic acetylcholine- and N-methyl-D-aspartate receptor levels.

Tg 2576 (APPswe) mice develop age-related amyloid deposition as well as behavioural- and electrophysiological changes in the brain. In this study, APPswe mice were investigated from 7 to 90 days of age. We observed high Abeta levels in the cortex of APPswe mice at 7 days of age, suggesting that these mice produce Abeta from birth. A positive correlation between Abeta and synaptophysin levels, followed by changes in ERK MAPK activity, indicated that Abeta causes altered synaptic function and an increase in the number of synaptic terminals. In addition, alterations in [(125)I]alphabungarotoxin- and [(3)H]MK-801 binding sites were also observed in APPswe mice compared to controls. In conclusion, over-expression of Abeta early in life causes changes in synaptophysin levels and number of [(125)I]alphabungarotoxin- and [(3)H]MK-801 binding sites. The results may provide important information about the onset and consequences of Abeta pathology in this transgenic mouse model.

Elevated levels of Abeta1-40 and Abeta1-42 do not alter the binding sites of nicotinic receptor subtypes in the brain of APPswe and PS1 double transgenic mice.

The binding sites of nicotinic acetylcholine receptor (nAChR) subtypes were measured in the parietal cortex and hippocampus of transgenic mice carrying mutant human APPswe and presenilin 1 (PS1) genes (APPswe/PS1 mice) between the ages of 3 weeks and 17 months. Soluble and insoluble beta-amyloid peptide (Abeta1-40 and Abeta1-42) levels were investigated in parallel. No significant differences in binding sites of [(3)H]cytisine (alpha4beta2 nAChRs) and [(125)I]alpha-bungarotoxin (alpha7 nAChRs) were observed in APPswe/PS1 mice and wild-type control mice at any age studied. At three weeks of age, soluble Abeta1-40 was detectable in the parietal cortex and hippocampus of APPswe/PS1 mice, whereas Abeta1-42 was detectable from 12 months of age. A pronounced increase in insoluble Abeta1-42 was observed between 3 weeks and 17 months compared with that of insoluble Abeta1-40 in both brain regions, indicating a shift that favors accumulation of Abeta1-42 in older APPswe/PS1 mice. The findings indicate that elevated Abeta levels in the brains of APPswe/PS1 mice do not alter the number of alpha4beta2 and alpha7 receptors, the two major brain nAChR subtypes.