Central cholinergic functions in human amyloid precursor protein knock-in/presenilin-1 transgenic mice.

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.

• Authors: J Hartmann, C Erb, U Ebert, K H Baumann, A Popp, G König, J Klein
• Journal: Neuroscience (Neuroscience) Vol. 125 Issue 4 Pg. 1009-17 ( 2004) ISSN: 0306-4522 [Print] United States
• PMID: 15120860 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Membrane Proteins
• Muscarinic Antagonists
• PSEN1 protein, human
• Presenilin-1
• Scopolamine
• Acetylcholine

Topics

• Acetylcholine (analysis, metabolism)
• Alzheimer Disease (genetics, metabolism, pathology)
• Amyloid beta-Peptides (metabolism)
• Amyloid beta-Protein Precursor (genetics)
• Animals
• Behavior, Animal (drug effects, physiology)
• Brain (drug effects, pathology)
• Disease Models, Animal
• Extracellular Fluid (chemistry)
• Humans
• Membrane Proteins (genetics)
• Mice
• Mice, Transgenic
• Microdialysis
• Muscarinic Antagonists (pharmacology)
• Mutation
• Neurons (metabolism)
• Plaque, Amyloid (pathology)
• Presenilin-1
• Scopolamine (pharmacology)