Title page Neurotransmitters and Energy Metabolites in Amyloid-bearing APP SWE x PSEN1dE9 Mouse Brain JPET #161091 2 Running title page Running title: Influence of amyloid on brain neurochemistry Correspondence

Abstract

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 APP SWE x PSEN1dE9 mouse. At 10-14 months of age, these mice had high levels of amyloid peptides (6.6 µg/g wet wt.) and widespread amyloid plaques. Extracellular levels of acetylcholine were determined by microdialysis in the hippocampus and were comparable to non-transgenic mice from the same colony. In the open field, both mouse strains responded with a threefold increase of hippocampal acetylcholine release. Exploratory behavior of the transgenic mice appeared normal. Infusion of scopolamine evoked 5-6fold increases of acetylcholine levels in both mouse strains. High-affinity choline uptake (HACU) and cholinesterase activities were identical in both mouse lines. Extracellular levels of glucose and glycerol were similar in control and transgenic mice while 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 while infusion of scopolamine (1 µM) increased glucose but not lactate. Glutamate levels were increased by scopolamine while glycerol remained constant under all 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. JPET #161091