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The Journal of Neuroscience, February 1, 2006, 26(5):1343-1354; doi:10.1523/JNEUROSCI.4236-05.2006

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Neurobiology of Disease
Locus Ceruleus Degeneration Promotes Alzheimer Pathogenesis in Amyloid Precursor Protein 23 Transgenic Mice

Michael T. Heneka,¹ Mutiah Ramanathan,¹ Andreas H. Jacobs,³ Lucia Dumitrescu-Ozimek,¹ Andras Bilkei-Gorzo,² Thomas Debeir,⁴ Magdalena Sastre,¹ Norbert Galldiks,³ Andreas Zimmer,² Mathias Hoehn,³ Wolf-Dieter Heiss,³ Thomas Klockgether,¹ and Matthias Staufenbiel⁵

¹Departments of Neurology and ²Psychiatry, University of Bonn, 53127 Bonn, Germany, ³Max Planck Institute for Neurological Research, Department of Neurology and Center for Molecular Medicine, University of Cologne, 50931 Cologne, Germany, ⁴National Institute of Health and of Medical Research Unit 679, Neurology and Experimental Therapeutics, Salpêtrière Hospital, 75651 Paris, France, and ⁵Novartis Institutes for Biomedical Research Basel, 4002 Basel, Switzerland

Correspondence should be addressed to Dr. Michael T. Heneka, Department of Neurology, University of Münster, Albert Schweitzer Strasse 33, 48149 Münster, Germany. Email: heneka{at}uni-muenster.de

Locus ceruleus (LC) degeneration and loss of cortical noradrenergic innervation occur early in Alzheimer’s disease (AD). Although this has been known for several decades, the contribution of LC degeneration to AD pathogenesis remains unclear. We induced LC degeneration with N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (dsp4) in amyloid precursor protein 23 (APP23) transgenic mice with a low amyloid load. Then 6 months later the LC projection areas showed a robust elevation of glial inflammation along with augmented amyloid plaque deposits. Moreover, neurodegeneration and neuronal loss significantly increased. Importantly, the paraventricular thalamus, a nonprojection area, remained unaffected. Radial arm maze and social partner recognition tests revealed increased memory deficits while high-resolution magnetic resonance imaging-guided micro-positron emission tomography demonstrated reduced cerebral glucose metabolism, disturbed neuronal integrity, and attenuated acetylcholinesterase activity. Nontransgenic mice with LC degeneration were devoid of these alterations. Our data demonstrate that the degeneration of LC affects morphology, metabolism, and function of amyloid plaque-containing higher brain regions in APP23 mice. We postulate that LC degeneration substantially contributes to AD development.

Key words: degeneration; neuroinflammation; microglia; astroglia; locus ceruleus; neuronal death

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Received April 6, 2005; revised Nov. 30, 2005; accepted Dec. 6, 2005.

Correspondence should be addressed to Dr. Michael T. Heneka, Department of Neurology, University of Münster, Albert Schweitzer Strasse 33, 48149 Münster, Germany. Email: heneka{at}uni-muenster.de

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