Dexefaroxan reverses cognitive and affective phenotypes in TgCRND8 mice
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1
University of Toronto, Department of Physiology, Canada
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2
University of Toronto, Centre for Research in Neurodegenerative Diseases, Canada
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3
University of Toronto, Institute of Medical Science, Canada
Noradrenergic deficits may be key to the pathogenesis and behavioural presentation of Alzheimer’s disease (AD). We assessed monoamine levels and turnover by HPLC and electrochemical detection in the amyloid precursor protein (APP)-transgenic TgCRND8 mouse model of AD. We found that pre-plaque, 4-week-old TgCRND8 mice exhibit selective reductions in noradrenaline in the hippocampus, temporoparietal and frontal cortices, and cerebellum. Analyses in older mice revealed the noradrenergic deficit to be progressive. No reductions were observed in dopamine. However, serotonin and its 5-HIAAA metabolite were increased in the striatum and brainstem of aged plaque-bearing mice. To assess how altered transmitter levels might influence phenotypes, we examined cognition and affect. Pre-plaque, 8-week-old TgCRND8 mice had significant cortical, short-term memory deficits in an object recognition task. By this age, they also exhibited progressive behavioural despair in a tail suspension test, shown sensitive to antidepressants that increase noradrenergic transmission. At 24 weeks, TgCRND8 mice were less anxious than littermate controls in the zero maze. To test whether the loss of noradrenergic tone in major terminal fields caused these behavioural phenotypes, we examined the effect of replenishing noradrenaline. Dexefaroxan (Pierre Fabre Inc.) enhances noradrenergic transmission by antagonizing presynaptic inhibitory α2-adrenoceptors. Mini-osmotic pumps, delivering dexefaroxan, saline or rivastigmine (Exelon™: Novartis Inc.), a cholinesterase inhibitor, were implanted subcutaneously in 12-week-old mice for 28 days. Both dexefaroxan and rivastigmine ameliorated object memory deficits and behavioural despair. Noradrenaline can affect cortical plasticity by increasing acetylcholine release. Dexefaroxan facilitates this release by blocking inhibitory α2-adrenoceptors on cholinergic terminals. Neither dexefaroxan, nor rivastigmine altered anxiety, a parameter that may depend more upon striatal serotonin levels. In sum, we have shown that noradrenergic deficits precede plaque deposition and behavioural impairment in a robust amyloid-based mouse model of AD. Targeting the noradrenergic deficit early in the disease process may mitigate amyloid-induced functional impairment.
Conference:
B.R.A.I.N. platform in Physiology poster day 2009, Toronto, ON, Canada, 16 Dec - 16 Dec, 2009.
Presentation Type:
Poster Presentation
Topic:
Poster presentations
Citation:
Francis
BM,
Yang
J and
Mount
HT
(2009). Dexefaroxan reverses cognitive and affective phenotypes in TgCRND8 mice.
Front. Neurosci.
Conference Abstract:
B.R.A.I.N. platform in Physiology poster day 2009.
doi: 10.3389/conf.neuro.03.2009.17.012
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Received:
16 Dec 2009;
Published Online:
16 Dec 2009.
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Correspondence:
Beverly M Francis, University of Toronto, Department of Physiology, Toronto, Canada, beverly.francis@utoronto.ca