Locus coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer's disease
Abstract
Neurofibrillary degeneration in the nucleus basalis and a loss of its cortical cholinergic projections are prominent components of the neuropathology in Alzheimer's disease (AD). The AD brain is also associated with a degeneration of the noradrenergic projections arising from the nucleus locus coeruleus (LC), but the time course of this lesion is poorly understood. To determine whether the LC displays neurofibrillary abnormalities early in the course of events leading to AD, we examined tissue specimens from seven cognitively normal controls and five subjects at the stages of mild cognitively impairment (MCI) or early AD. Tyrosine hydroxylase immunochemistry was used as a marker of LC neurons while AT8 immunolabeling visualized abnormal tau associated with neurofibrillary tangles and their precursors. Thioflavine-S was used as a marker for fully developed tangles. We found that AT8-positive labeling and thioflavine-S positive tangles were present in both groups of specimens. However, the percentage of neurons containing each of these markers was significantly higher in the cognitively impaired group. The MMSE scores displayed a negative correlation with both markers of cytopathology. These results indicate that cytopathology in the LC is an early event in the age-MCI-AD continuum and that it may be listed among the numerous factors that mediate the emergence of the cognitive changes leading to dementia.
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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 [42]
As AD progresses, the NFTs become numerous in locus coeruleus which may suggest the same pathogenetic process is becoming more severe.
“As AD progresses, the NFTs become numerous in locus coeruleus which may suggest the same pathogenetic process is becoming more severe (301).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [301]
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- Authors
- Grudzien, A., Shaw, P., Weintraub, S., Bigio, E., Mash, D. C., & Mesulam, M. M.
- Affiliations
- Northwestern University (US)
- University of Miami (US)
- Corresponding author
- Mesulam, M. Marsel
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2007-03
- Volume
- 28
- Issue
- 3
- Pages
- 327-335
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2168697938
- Cited by
- 396
- References
- 45
- Citations by year
- 2026: 17 · 2025: 21 · 2024: 19 · 2023: 31 · 2022: 19 · 2021: 40 · 2020: 30 · 2019: 16 · 2018: 15 · 2017: 28 · 2016: 18 · 2015: 22 · 2014: 18 · 2013: 20 · 2012: 20
- FWCI
- 6.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Miami
- Northwestern University
- National Institute on Aging (P30AG013854)
- 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
- locus coeruleus, neurofibrillary degeneration, Alzheimer's disease, mild cognitive impairment, aging, tau protein, neurofibrillary tangles, noradrenergic projections, AT8, thioflavine S, tyrosine hydroxylase, cognitive decline, dementia
- MeSH terms
- Acetylcholinesterase, Aged, Aged, 80 and over, Aging, Alzheimer Disease, Cognition Disorders, Female, Humans, Immunohistochemistry, Locus Coeruleus, Male, Middle Aged, Postmortem Changes, Psychological Tests, Reference Values, Tyrosine 3-Monooxygenase, Neurofibrillary Tangles, tau Proteins, Statistics, Nonparametric
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