Locus Coeruleus Ablation Exacerbates Cognitive Deficits, Neuropathology, and Lethality in P301S Tau Transgenic Mice
Open accessAbstract
The brainstem locus coeruleus (LC) supplies norepinephrine to the forebrain and degenerates in Alzheimer's disease (AD). Loss of LC neurons is correlated with increased severity of other AD hallmarks, including β-amyloid (Aβ) plaques, tau neurofibrillary tangles, and cognitive deficits, suggesting that it contributes to the disease progression. Lesions of the LC in amyloid-based transgenic mouse models of AD exacerbate Aβ pathology, neuroinflammation, and cognitive deficits, but it is unknown how the loss of LC neurons affects tau-mediated pathology or behavioral abnormalities. Here we investigate the impact of LC degeneration in a mouse model of tauopathy by lesioning the LC of male and female P301S tau transgenic mice with the neurotoxin N-(2-chloroethyl) -N- ethyl-bromobenzylamine (DSP-4) starting at 2 months of age. By 6 months, deficits in hippocampal-dependent spatial (Morris water maze) and associative (contextual fear conditioning) memory were observed in lesioned P301S mice while performance remained intact in all other genotype and treatment groups, indicating that tau and LC degeneration act synergistically to impair cognition. By 10 months, the hippocampal neuroinflammation and neurodegeneration typically observed in unlesioned P301S mice were exacerbated by DSP-4, and mortality was also accelerated. These DSP-4-induced changes were accompanied by only a mild aggravation of tau pathology, suggesting that increased tau burden cannot fully account for the effects of LC degeneration. Combined, these experiments demonstrate that loss of LC noradrenergic neurons exacerbates multiple phenotypes caused by pathogenic tau, and provides complementary data to highlight the dual role LC degeneration has on both tau and Aβ pathologies in AD. SIGNIFICANCE STATEMENT Elucidating the mechanisms underlying AD is crucial to developing effective diagnostics and therapeutics. The degeneration of the LC and loss of noradrenergic transmission have been recognized as ubiquitous events in AD pathology, and previous studies demonstrated that LC lesions exacerbate pathology and cognitive deficits in amyloid-based mouse models. Here, we reveal a complementary role of LC degeneration on tau-mediated aspects of the disease by using selective lesions of the LC and the noradrenergic system to demonstrate an exacerbation of cognitive deficits, neuroinflammation, neurodegeneration in a transgenic mouse model of tauopathy. Our data support an integral role for the LC in modulating the severity of both canonical AD-associated pathologies, as well as the detrimental consequences of LC degeneration during disease progression.
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The presence of spatial memory deficits in the PS19 line is controversial, with some studies pointing towards deficits in the MWM test from 5 or 6.5 months, while others report initial deficits in spatial memory at 10 or 12 months of age.
“The presence of spatial memory deficits in the PS19 line is controversial, with some studies pointing towards the development of deficits in the MWM test from a relatively young age of 5 [28] or 6.5 months [41], while others report initial deficits in spatial memory at 10 [42] or even 12 months of age [29], respectively.”
From Characterization of a Mouse Model of Alzheimer’s Disease Expressing Aβ4-42 and Human Mutant Tau (2021) · cites this paper as [42]
The Morris water maze Results (page unavailable) show that unlesioned P301S mice learned at 4 and 6 months but did not show significant learning at 10 months, supporting the age attributed to this source. The same section reports that only P301S mice with LC lesions showed a significant probe-trial memory deficit at 10 months; it does not establish a spatial memory-recall deficit in the unlesioned PS19 line at that age. The 5-, 6.5-, and 12-month findings are attached to other citations in the citing sentence. (LLM, conf=0.84)
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“5 months [41], while others report initial deficits in spatial memory at 10 [42] or even 12 months of age [29], respectively.”
Background
- Authors
- Chalermpalanupap, T., Schroeder, J. P., Rorabaugh, J. M., Liles, L. C., Lah, J. J., Levey, A. I., & Weinshenker, D.
- Affiliations
- Emory University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2017-11-13
- Volume
- 38
- Issue
- 1
- Pages
- 74-92
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC5761438
- OpenAlex
- W2768574326
- Cited by
- 136
- References
- 14
- Citations by year
- 2026: 14 · 2025: 13 · 2024: 22 · 2023: 14 · 2022: 20 · 2021: 22 · 2020: 11 · 2019: 13 · 2018: 6 · 2017: 1
- FWCI
- 6.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association (IIRG-13-278692)
- National Institutes of Health (IIRG-13-278692, AG025688)
- National Institute on Aging (RF1AG047667, P50AG025688)
- National Institute of Neurological Disorders and Stroke (P30NS055077)
- 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, noradrenergic neurons, P301S tau transgenic mice, tauopathy, Alzheimer's disease, cognitive impairment, spatial memory, contextual fear conditioning, hippocampal inflammation, neurodegeneration, tau pathology, norepinephrine, sex differences, mortality, amyloid plaques, neurofibrillary tangles
- MeSH terms
- Animals, Benzylamines, Cognition Disorders, Conditioning, Psychological, Fear, Female, Genes, Lethal, Hippocampus, Inflammation, Locus Coeruleus, Male, Memory Disorders, Mice, Inbred C57BL, Mice, Transgenic, Norepinephrine, tau Proteins, Maze Learning, Tauopathies, Mice
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