Amyloid beta-Protein Precursor; Vesicular Acetylcholine Transport Proteins; Peroxynitrous Acid; Nitric Oxide Synthase Type II; Norepinephrine; Alzheimer Disease/diagnostic imaging; Alzheimer Disease/etiology; Alzheimer Disease/pathology; Amyloid beta-Protein Precursor/genetics; Animals; Astrocytes/metabolism; Brain/diagnostic imaging; Cognition Disorders/etiology; Female; Locus Coeruleus/metabolism; Locus Coeruleus/pathology; Mice; Mice, Transgenic; Microglia/metabolism; Nerve Degeneration/pathology; Nitric Oxide Synthase Type II/metabolism; Norepinephrine/metabolism; Peroxynitrous Acid/metabolism; Plaque, Amyloid/pathology; Positron-Emission Tomography; Vesicular Acetylcholine Transport Proteins/metabolism; Astroglia; Degeneration; Locus ceruleus; Microglia; Neuroinflammation; Neuronal death; Neuroscience (all); General Neuroscience
Abstract :
[en] 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.
Disciplines :
Neurology
Author, co-author :
HENEKA, Michael ; Department of Neurology, University of Bonn, 53127 Bonn, Germany. heneka@uni-muenster.de
Ramanathan, Mutiah; Department of Neurology, University of Bonn, 53127 Bonn, Germany
Jacobs, Andreas H; Max Planck Institute for Neurological Research, Department of Neurology and Center for Molecular Medicine, University of Cologne, 50931 Cologne, Germany
Dumitrescu-Ozimek, Lucia; Department of Neurology, University of Bonn, 53127 Bonn, Germany
Bilkei-Gorzo, Andras; Department of Psychiatry, University of Bonn, 53127 Bonn, Germany
Debeir, Thomas; National Institute of Health and of Medical Research Unit 679, Neurology and Experimental Therapeutics, Salpêtrière Hospital, 75651 Paris, France
Sastre, Magdalena; Department of Neurology, University of Bonn, 53127 Bonn, Germany
Galldiks, Norbert; Max Planck Institute for Neurological Research, Department of Neurology and Center for Molecular Medicine, University of Cologne, 50931 Cologne, Germany
Zimmer, Andreas; Department of Psychiatry, University of Bonn, 53127 Bonn, Germany
Hoehn, Mathias; Max Planck Institute for Neurological Research, Department of Neurology and Center for Molecular Medicine, University of Cologne, 50931 Cologne, Germany
Heiss, Wolf-Dieter; Max Planck Institute for Neurological Research, Department of Neurology and Center for Molecular Medicine, University of Cologne, 50931 Cologne, Germany
Klockgether, Thomas; Department of Neurology, University of Bonn, 53127 Bonn, Germany
Staufenbiel, Matthias; Novartis Institutes for Biomedical Research Basel, 4002 Basel, Switzerland
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