Reduced Tissue Levels of Noradrenaline Are Associated with Behavioral Phenotypes of the TgCRND8 Mouse Model of Alzheimer's Disease

Noradrenergic cell loss is well documented in Alzheimer's disease (AD). We have measured the tissue levels of catecholamines in an amyloid precursor protein-transgenic 'TgCRND8' mouse model of AD and found reductions in noradrenaline (NA) within hippocampus, temporoparietal and frontal cortices, and cerebellum. An age-related increase in cortical NA levels was observed in non-Tg controls, but not in TgCRND8 mice. In contrast, NA levels declined with aging in the TgCRND8 hippocampus. Dopamine levels were unaffected. Reductions in the tissue content of NA were found to coincide with altered expression of brain-derived neurotrophic factor (BDNF) mRNA and to precede the onset of object memory impairment and behavioral despair. To test whether these phenotypes might be associated with diminished NA, we treated mice with dexefaroxan, an antagonist of presynaptic inhibitory alpha(2)-adrenoceptors on noradrenergic and cholinergic terminals. Mice 12 weeks of age were infused systemically for 28 days with dexefaroxan or rivastigmine, a cholinesterase inhibitor. Both dexefaroxan and rivastigmine improved TgCRND8 behavioral phenotypes and increased BDNF mRNA expression without affecting amyloid-beta peptide levels. Our results highlight the importance of noradrenergic depletion in AD-like phenotypes of TgCRND8 mice. Neuropsychopharmacology (2012) 37, 1934-1944; doi:10.1038/npp.2012.40; published online 11 April 2012