Abstract
Alzheimer's disease is characterized by amyloid peptide formation and deposition, neurofibrillary tangles, synaptic loss and central cholinergic dysfunction, dysfunction of energy metabolism, and dementia; however, the interactions between these hallmarks remain poorly defined. We studied a well characterized mouse model of amyloid deposition, the doubly transgenic APPSWE×PSEN1dE9 mouse. At 10 to 14 months of age, these mice had high levels of amyloid peptides (6.6 μg/g wet weight) and widespread amyloid plaques. Extracellular levels of acetylcholine (ACh) were determined by microdialysis in the hippocampus and were comparable with nontransgenic mice from the same colony. In the open field, both mouse strains responded with a 3-fold increase of hippocampal ACh release. Exploratory behavior of the transgenic mice appeared normal. Infusion of scopolamine evoked 5- to 6-fold increases of ACh levels in both mouse strains. High-affinity choline uptake and cholinesterase activities were identical in both mouse lines. Extracellular levels of glucose and glycerol were similar in control and transgenic mice, whereas lactate levels were slightly (p = 0.06) and glutamate levels significantly (p = 0.02) lower in transgenic mice. Exploration caused increases of glucose and lactate, whereas infusion of scopolamine (1 μM) increased glucose but not lactate. Glutamate levels were increased by scopolamine, whereas glycerol remained constant under all the conditions. We conclude that amyloid peptide production and plaque deposition causes minor changes in cholinergic function and energy metabolites in transgenic mice in vivo. Amyloid peptide formation and/or deposition may not be sufficient for long-term cholinergic or metabolic dysfunction.
Footnotes
This work was supported by the Alzheimer's Association [Grant IIRG-04-1178].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.161091
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ABBREVIATIONS:
- AD
- Alzheimer's disease
- AChE
- acetylcholinesterase
- APP
- amyloid precursor protein
- PS
- presenilin
- ACh
- acetylcholine
- HACU
- high-affinity choline uptake
- ELISA
- enzyme-linked immunosorbent assay
- aCSF
- artificial cerebrospinal fluid
- ANOVA
- analysis of variance.
- Received August 27, 2009.
- Accepted October 21, 2009.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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