NEURONAL DEGENERATION IN LOCUS CERULEUS AND CORTICAL CORRELATES OF ALZHEIMER DISEASE
Abstract
Relationships were examined between neuronal degeneration in the nucleus locus ceruleus (nLC), a parameter of central noradrenergic impairment, and neocortical markers of Alzheimer disease (AD). The loss of nLC neurons was found to correlate significantly with norepinephrine concentration, choline acetyltransferase (ChAT) activity, and numbers of plaques and tangles on Brodmann area 24 (cingulate); ChAT and plaque counts in area 21 (temporal); and with ChAT activity in area 10 (frontal). In addition, nLC neuronal counts were correlated significantly with the severity and estimated duration of dementia. The number of neurofibrillary tangles in nLC, which did not correlate significantly with neocortical markers of AD, correlated with the estimated duration and severity of dementia. These data suggest that changes in central noradrenergic pathways are related to the pathophysiology of AD.
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The locus coeruleus is the first site of pathology in AD subjects, with neurofibrillary tangles preceding cortical tau or Aβ deposits.
“Subsequent studies identified the locus coeruleus as the first site of pathology in AD subjects, with NFTs preceding cortical tau or Aβ deposits [41–43].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [43]
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“Indeed, deposits of neurofibrillary tangles and extensive tissue loss occur in the LC and have been found to correlate with disease duration and symptom severity (Bondareff et al., 1987; German, White, & Sparkman, 1987, 1992; Grudzien et al., 2007).”
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“It has also been reported that neuronal LC loss and degeneration of noradrenergic axons lead to decreased NA levels in the respective projection areas (Adolfsson et al., 1979; Iversen et al., 1983), and several studies demonstrated a correlation of LC cell death (or decreased cortical NA) levels with severity and dura…”
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“In AD patients, the degeneration of LC neurons highly correlates with the severity of dementia (Bondareff et al., 1987; Zarow et al., 2003).”
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German, D. C., Nelson, O. L., Liang, F., Liang, C., & Games, D. (2005) · The Journal of Comparative Neurology · doi:10.1002/cne.20744 · Cited by 50 · see citing works
A Noradrenergic Lesion Exacerbates Neurodegeneration in a Down Syndrome Mouse Model
Lockrow, J. P., Boger, H. A., Gerhardt, G. A., Aston‐Jones, G., Bachman, D., & Granholm, A. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-101218 · Cited by 49 · see citing works
“The loss of LC neurons correlates with dementia severity, as well as amyloid plaques and neurofibrillary tangles [4].”
Tiernan, C. T., Ginsberg, S. D., He, B., Ward, S., Guillozet-Bongaarts, A. L., Kanaan, N. M., Mufson, E. J., & Counts, S. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.05.021 · Cited by 47 · see citing works
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Sleep Disturbances in MCI and AD: Neuroinflammation as a Possible Mediating Pathway
Pak, V. M., Onen, S. ‐., Bliwise, D. L., Kutner, N. G., Russell, K. L., & Onen, F. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00069 · Cited by 49 · see citing works
The role of the locus coeruleus in shaping adaptive cortical melodies
Wainstein, G., Müller, E. J., Taylor, N. L., Munn, B., & Shine, J. M. (2022) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2022.03.006 · Cited by 45 · see citing works
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“Interestingly, reduced cortical NA levels significantly correlate with the numbers of Ab plaques, neurofibrillary tangles, and the severity of dementia in AD (Mann et al. 1982; Bondareff et al. 1987).”
BackgroundInfluentialThe Role of Th17 in Neuroimmune Disorders: A Target for CAM Therapy. Part III
Vojdani, A., Lambert, J., & Kellermann, G. H. (2009) · Evidence-based Complementary and Alternative Medicine · doi:10.1093/ecam/nep064 · Cited by 47 · see citing works
“Increased NE, acting centrally, can contribute to the release of antiinflammatory cytokines, whereas low concentrations support a proinflammatory biological state (89,90).”
BackgroundScullion, G. A., Kendall, D. A., Marsden, C. A., Sunter, D., & Pardon, M. (2010) · Neuropharmacology · doi:10.1016/j.neuropharm.2010.09.002 · Cited by 44 · see citing works
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Microglial CX3CR1 production increases in Alzheimer's disease and is regulated by noradrenaline
González-Prieto, M., Gutiérrez, I. L., García-Bueno, B., Caso, J., Leza, J., Ortega-Hernández, A., Gómez-Garre, D., & Madrigal, J. (2020) · Glia · doi:10.1002/glia.23885 · Cited by 37 · see citing works
“…actions of NA have also been confirmed in different studies using NA-depleting (Hammerschmidt et al., 2013; Heneka et al., 2002) and NA-elevating strategies (Braun & Feinstein, 2019; F IGURE 11 Flow cytometry analysis of noradrenaline (NA) effect on CX3CR1 synthesis in primary microglia cultures.”
ResultHormone therapy and Alzheimer?s disease: benefit or harm?
Henderson, V. W. (2004) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.5.2.389 · Cited by 45 · see citing works
“Cholinergic neurons [53] are vulnerable to neurofibrillary tangle formation, as are noradrenergic [54] and serotonergic [55] neurons.”
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“In addition to cholinergic alterations, the pathophysiological changes of central catecholaminergic pathways were also reported to contribute to the memory loss in animal models and Alzheimer’s disease patients (Davies and Maloney, 1976; Coyle et al., 1983; Arnsten and Goldman-Rakic, 1985; Price et al., 1985; Bondaref…”
BackgroundCaligiore, D., Giocondo, F., & Silvetti, M. (2022) · IBRO Neuroscience Reports · doi:10.1016/j.ibneur.2022.09.007 · Cited by 36 · see citing works
Janssens, J., Vermeiren, Y., Fransén, E., Aerts, T., Dam, D. V., Engelborghs, S., & Deyn, P. P. D. (2018) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1016/j.dadm.2018.01.002 · Cited by 36 · see citing works
Morawski, M., Hartlage‐Rübsamen, M., Jäger, C., Waniek, A., Schilling, S., Schwab, C., McGeer, P. L., Arendt, T., Demuth, H., & Roßner, S. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0685-y · Cited by 37 · see citing works
“In AD, in addition to neocortical and hippocampal neurodegeneration and Ab plaque pathology, there is a selective loss of defined neuronal populations in distinct subcortical brain nuclei, including the nucleus basalis Meynert (NbM) of the cholinergic basal forebrain [2, 9, 70], the Edinger–Westphal nucleus (EWN) [21,…”
BackgroundResultPolak, P. E., Kalinin, S., Braun, D. J., Sharp, A. J., Lin, S. X., & Feinstein, D. L. (2012) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2012.07673.x · Cited by 35 · see citing works
Wu, S. Z., Masurkar, A. V., & Balcer, L. J. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.572337 · Cited by 35 · see citing works
Mercan, D., & Heneka, M. T. (2022) · Biology · doi:10.3390/biology11121822 · Cited by 34 · see citing works
“There have been numerous studies which suggest a correlation of the LC degeneration with Aβ plaque load in the brain, NFTs and the severity of dementia [138].”
BackgroundChong, Y. H., Shin, Y. J., & Suh, Y. (2003) · Molecular Pharmacology · doi:10.1124/mol.63.3.690 · Cited by 34 · see citing works
“Finally, the severity and duration of dementia in AD are significantly correlated with the early loss of locus ceruleus neurons (Bondareff et al., 1987; German et al., 1992), leading to decreased levels of cortical norepinephrine, which can negatively regulate inflammatory events in brain cells although the up-regulat…”
BackgroundIs Elevated Norepinephrine an Etiological Factor in Some Cases of Alzheimers Disease?
Fitzgerald, P. J. (2010) · Current Alzheimer Research · doi:10.2174/156720510792231775 · Cited by 32 · see citing works
“Loss of LC neurons in AD was also examined by this group of researchers and was found to correlate with NE concentration, number of plaques and tangles in cingulate cortex, and severity and estimated duration of dementia [14].”
Backgroundβ1‐adrenergic receptor activation enhances memory in Alzheimer's disease model
Coutellier, L. D., Ardestani, P. M., & Shamloo, M. (2014) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.57 · Cited by 31 · see citing works
“A well-defined pathological hallmark of AD is the degeneration of the neurons in the locus coeruleus, the main source of noradrenaline (NA) in the brain.(8,9) This degeneration is associated with a subsequent reduction in NA and reduced activation of the adrenergic receptors.”
BackgroundFan, Y., Huang, J., Duffourc, M. M., et al. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.07.005 · Cited by 29 · see citing works
Computational Modeling of Catecholamines Dysfunction in Alzheimer’s Disease at Pre-Plaque Stage
Caligiore, D., Silvetti, M., D’Amelio, M., Puglisi‐Allegra, S., & Baldassarre, G. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-200276 · Cited by 28 · see citing works
Beta-adrenergic stimulation suppresses phagocytosis via Epac activation in murine microglial cells
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Sakakibara, Y., Hirota, Y., Ibaraki, K., Takei, K., Chikamatsu, S., Tsubokawa, Y., Saito, T., Saido, T. C., Sekiya, M., & Iijima, K. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210385 · Cited by 26 · see citing works
Chong, Y. H., Shin, S. A., Lee, H. J., Kang, J. H., & Suh, Y. (2002) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(02)00349-1 · Cited by 26 · see citing works
Associations between MRI-assessed locus coeruleus integrity and cortical gray matter microstructure
Elman, J. A., Puckett, O. K., Hagler, D. J., Pearce, R. C., Fennema‐Notestine, C., Hatton, S. N., Lyons, M. J., McEvoy, L. K., Panizzon, M. S., Reas, E. T., et al. (2021) · Cerebral Cortex · doi:10.1093/cercor/bhab475 · Cited by 24 · see citing works
- Authors
- Bondareff, W., Mountjoy, C. Q., Roth, M., Rossor, M. N., Iversen, L. L., Reynolds, G. P., & Hauser, D. L.
- Affiliations
- University of Southern California (US)
- University of Cambridge (GB)
- Medical Research Council (GB)
- Venue
- Alzheimer Disease & Associated Disorders
- Published
- 1987
- Volume
- 1
- Issue
- 4
- Pages
- 256-262
- ISSN
- 0893-0341 (ISSN-L)
- OpenAlex
- W2053273884
- Cited by
- 166
- References
- 0
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 5 · 2023: 4 · 2022: 10 · 2021: 7 · 2020: 9 · 2019: 6 · 2018: 6 · 2017: 11 · 2016: 6 · 2015: 7 · 2014: 7 · 2013: 4 · 2012: 4
- FWCI
- 1.60
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Alzheimer Disease & Associated Disorders (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, locus coeruleus, neurodegeneration, noradrenergic pathways, norepinephrine, choline acetyltransferase, amyloid plaques, neurofibrillary tangles, dementia severity, neocortex, cingulate cortex, temporal cortex, frontal cortex
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Cell Count, Cerebral Cortex, Choline O-Acetyltransferase, Humans, Locus Coeruleus, Nerve Degeneration, Neurofibrils, Neurons, Norepinephrine
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