Noradreneline deficiency aggrevates learning and memory impairment independent of Aß Levels in APPPS1 mice

• Published in: Aktuelle Neurologie
• Main Authors: Hammerschmidt, T, Kummer, M.P, Gorji, A, Terwel, D, Weinshenker, D, Pape, H.C, Heneka, M.T
• Format: Conference Proceeding
• Language: English
• Published: 02.09.2008
• ISSN: 0302-4350; 1438-9428
• DOI: 10.1055/s-0028-1086716

Locus coeruleus (LC) degeneration and subsequent noradrenaline (NA) deficiency occur early in Alzheimers disease (AD) and may siginificantly precede amyloid-ß plaque and neurofibrillary tangle formation. The LC projects to areas that are affected in AD, including the hippocampus and enthorhinal cortex. While it is known that NA physiologically modulates long term potentiation (LTP), a cellular correlate of learning and memory, in the hippocampus, the consequences of LC degeneration on learning and memory are less clear. In the present study we used the APP/PS1 transgenic model an established model of AD, to test the impact of Aß plaque deposition on hippocampal LTP and the spatial memory performance in the Morris water maze test. In a further step we investigated the contribution of NA by crossing APP/PS1 mice with mice deficient for dopamine beta hydroxylase (DBH (-/-)) mice. Mice were also analyzed for all steps of APP processing and amyloid-ß deposition. Both, APP/PS1 and DBH (-/-) mice show an impairment in early and late stages of LTP. However, APPPS1/DBH(-/-) mice reveal the strongest reduction in LTP. Deterioration of LTP was paralleled by the cognitive performance in the Morris water maze. While escape latencies were significantly increased in the APP/PS1 and DBH(-/-) mice, APPPS1/DBH(-/-) performed significantly worse. Analysis of APP processing as well as Aß1–40 and Aß1–42 levels showed no significant differences. Conclusion: APP/PS1 mutations reportedly inhibit the induction of LTP and impair learning and memory in the Morris water maze. These effects are dramatically aggravated by NA depletion and seem to be independent of APP processing and Aß levels. Therefore the early degeneration of the LC in AD patients might significantly add to cognitive deficits and represent a therapeutic target.