Locus Ceruleus Degeneration Promotes Alzheimer Pathogenesis in Amyloid Precursor Protein 23 Transgenic Mice
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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.
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Lesioning the locus coeruleus pathway increases plaque pathology in terminal fields of the cerebral cortex.
“In contrast, lesioning of another projection pathway, that from the locus coeruleus, was reported to increase plaque pathology in terminal fields of the cerebral cortex [72].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [72]
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- Authors
- Heneka, M. T., Ramanathan, M., Jacobs, A. H., Dumitrescu-Ozimek, L., Bilkei-Gorzo, A., Debeir, T., Sastre, M., Galldiks, N., Zimmer, A., Hoehn, M., Heiss, W.-D., Klockgether, T., & Staufenbiel, M.
- Affiliations
- University of Bonn (DE)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2006-02-01
- Volume
- 26
- Issue
- 5
- Pages
- 1343-1354
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6675491
- OpenAlex
- W2118414216
- Cited by
- 305
- References
- 54
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 18 · 2023: 21 · 2022: 23 · 2021: 18 · 2020: 16 · 2019: 16 · 2018: 12 · 2017: 20 · 2016: 9 · 2015: 17 · 2014: 11 · 2013: 17 · 2012: 19
- FWCI
- 7.31
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, other-oa)
- Max Planck Institute for Plasma Physics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (SFB400)
- International Brain Research Organization
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease pathogenesis, glial inflammation, amyloid plaques, neurodegeneration, memory impairment, brain glucose metabolism, acetylcholinesterase activity, paraventricular thalamus, cholinergic hypothesis
- MeSH terms
- Alzheimer Disease, Animals, Astrocytes, Brain, Cognition Disorders, Female, Locus Coeruleus, Mice, Transgenic, Nerve Degeneration, Norepinephrine, Amyloid beta-Protein Precursor, Microglia, Peroxynitrous Acid, Positron-Emission Tomography, Vesicular Acetylcholine Transport Proteins, Mice, Nitric Oxide Synthase Type II, Plaque, Amyloid
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