Central cholinergic functions in human amyloid precursor protein knock-in/presenilin-1 transgenic mice.
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.
Hartmann
J
J
Alzheimer Research Group, Bayer Health Care AG, D-42096 Wuppertal, Germany.
Erb
C
C
Ebert
U
U
Baumann
K H
KH
Popp
A
A
König
G
G
Klein
J
J
D000109:Acetylcholine / Q000032:analysis / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D004195:Disease Models, Animal; D045604:Extracellular Fluid / Q000737:chemistry; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D017551:Microdialysis; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D058225:Plaque, Amyloid / Q000473:pathology; D053764:Presenilin-1; D012601:Scopolamine / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D018727:Muscarinic Antagonists; C508853:PSEN1 protein, human; D053764:Presenilin-1; D012601:Scopolamine; D000109:Acetylcholine