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  • Title: Central cholinergic functions in human amyloid precursor protein knock-in/presenilin-1 transgenic mice.
    Author: Hartmann J, Erb C, Ebert U, Baumann KH, Popp A, König G, Klein J.
    Journal: Neuroscience; 2004; 125(4):1009-17. PubMed ID: 15120860.
    Abstract:
    Alzheimer's disease is characterized by amyloid peptide formation and deposition, neurofibrillary tangles, central cholinergic dysfunction, and dementia; however, the relationship between these parameters is not well understood. We studied the effect of amyloid peptide formation and deposition on central cholinergic function in knock-in mice carrying the human amyloid precursor protein (APP) gene with the Swedish/London double mutation (APP-SL mice) which were crossbred with transgenic mice overexpressing normal (PS1wt) or mutated (M146L; PS1mut) human presenilin-1. APP-SLxPS1mut mice had increased levels of Abeta peptides at 10 months of age and amyloid plaques at 14 months of age while APP-SLxPS1wt mice did not have increased peptide levels and did not develop amyloid plaques. We used microdialysis in 15-27 months old mice to compare hippocampal acetylcholine (ACh) levels in the two mouse lines and found that extracellular ACh levels were slightly but significantly reduced in the APP-SLxPS1mut mice (-26%; P=0.044). Exploratory activity in the open field increased hippocampal ACh release by two-fold in both mouse lines; total and relative increases were not significantly different for the two strains under study. Similarly, infusion of scopolamine (1 microM) increased hippocampal ACh release to a similar extent (3-5-fold) in both groups. High-affinity choline uptake, a measure of the ACh turnover rate, was identical in both mouse lines. Neurons expressing choline acetyltransferase were increased in the septum of APP-SLxPS1mut mice (+26%; P=0.046). We conclude that amyloid peptide production causes a small decrease of extracellular ACh levels. The deposition of amyloid plaques, however, does not impair stimulated ACh release and proceeds without major changes of central cholinergic function.
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