[en] Degeneration of locus ceruleus neurons and subsequent reduction of norepinephrine concentration in locus ceruleus projection areas represent an early pathological indicator of Alzheimer's disease. In order to model the pathology of the human disease and to study the effects of norepinephrine-depletion on amyloid precursor protein processing, behaviour, and neuroinflammation, locus ceruleus degeneration was induced in mice coexpressing the swedish mutant of the amyloid precursor protein and the presenilin 1 DeltaExon 9 mutant (APP/PS1) using the neurotoxin N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (dsp4) starting treatment at 3 months of age. Norepinephrine transporter immunolabelling demonstrated severe loss of locus ceruleus neurons and loss of cortical norepinephrine transporter starting as early as 4.5 months of age and aggravating over time. Of note, dsp4-treated transgenic mice showed elevated amyloid beta levels and impaired spatial memory performance at 6.5 months of age compared to control-treated APP/PS1 transgenic mice, indicating an accelerating effect on cerebral amyloidosis and cognitive deficits. Likewise, norepinephrine-depletion increased neuroinflammation compared to transgenic controls as verified by macrophage inflammatory protein-1alpha and -1beta gene expression analysis. Exploratory activity and memory retention was compromised by age in APP/PS1 transgenic mice and further aggravated by induced noradrenergic deficiency. In contrast, novel object recognition was not influenced by norepinephrine deficiency, but by the APP/PS1 transgene at 12 months. Overall, our data indicate that early loss of noradrenergic innervation promotes amyloid deposition and modulates the activation state of inflammatory cells. This in turn could have had impact on the acceleration of cognitive deficits observed over time.
We thank Michael Hermes for his scientific advice regarding behavioural studies and Manuela Brand for excellent technical support. The authors thank Jochen Walter for the generous gift of the 140 antibody directed against APP. The investigations were funded by Bayer Schering Pharma AG, Berlin, Germany.
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