The DOI matches its Crossref record; 46 of the 46 references it cites were found in a registry or an index.
Tau pathology spread in PS19 tau transgenic mice following locus coeruleus (LC) injections of synthetic tau fibrils is determined by the LC's afferent and efferent connections
Open accessAbstract
Filamentous tau inclusions are hallmarks of Alzheimer's disease (AD) and other neurodegenerative tauopathies. An increasing number of studies implicate the cell-to-cell propagation of tau pathology in the progression of tauopathies. We recently showed (Iba et al., J Neurosci 33:1024-1037, 2013) that inoculation of preformed synthetic tau fibrils (tau PFFs) into the hippocampus of young transgenic (Tg) mice (PS19) overexpressing human P301S mutant tau induced robust tau pathology in anatomically connected brain regions including the locus coeruleus (LC). Since Braak and colleagues hypothesized that the LC is the first brain structure to develop tau lesions and since LC has widespread connections throughout the CNS, LC neurons could be the critical initiators of the stereotypical spreading of tau pathology through connectome-dependent transmission of pathological tau in AD. Here, we report that injections of tau PFFs into the LC of PS19 mice induced propagation of tau pathology to major afferents and efferents of the LC. Notably, tau pathology propagated along LC efferent projections was localized not only to axon terminals but also to neuronal perikarya, suggesting transneuronal transfer of templated tau pathology to neurons receiving LC projections. Further, brainstem neurons giving rise to major LC afferents also developed perikaryal tau pathology. Surprisingly, while tangle-bearing neurons degenerated in the LC ipsilateral to the injection site starting 6 months post-injection, no neuron loss was seen in the contralateral LC wherein tangle-bearing neurons gradually cleared tau pathology by 6-12 months post-injection. However, the spreading pattern of tau pathology observed in our LC-injected mice is different from that in AD brains since hippocampus and entorhinal cortex, which are affected in early stages of AD, were largely spared of tau inclusions in our model. Thus, while our study tested critical aspects of the Braak hypothesis of tau pathology spread, this novel mouse model provides unique opportunities to elucidate mechanisms underlying the selective vulnerability of neurons to acquire tau pathology and succumb to or resist tau-mediated neurodegeneration.
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“As mice have primarily monocular vision, with >95% of RGCs projecting into the contralateral side of the brain, the unaffected side of the visual system can serve as an internal control 26, 27”
From Amyloid-beta induced retrograde axonal degeneration in a mouse tauopathy model (2019) · cites this paper as [27]
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Cites
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Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
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Self-citationSynapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model
Yoshiyama, Y., Higuchi, M., Zhang, B., Huang, S.-M., Iwata, N., Saido, T. C., Maeda, J., Suhara, T., Trojanowski, J. Q., & Lee, V. M.-Y. (2007) · Neuron · doi:10.1016/j.neuron.2007.01.010 · Cited by 2,208
Self-citationStages of the Pathologic Process in Alzheimer Disease: Age Categories From 1 to 100 Years
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Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders
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Metadata
- Authors
- Iba, M., McBride, J. D., Guo, J. L., Zhang, B., Trojanowski, J. Q., & Lee, V. M.-Y.
- Affiliations
- Hospital of the University of Pennsylvania (US)
- Corresponding author
- Lee, Virginia M.-Y.
- Venue
- Acta Neuropathologica
- Published
- 2015-07-07
- Volume
- 130
- Issue
- 3
- Pages
- 349-362
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC4545685
- OpenAlex
- W812488793
- Cited by
- 223
- References
- 46
- Citations by year
- 2026: 9 · 2025: 17 · 2024: 17 · 2023: 15 · 2022: 20 · 2021: 22 · 2020: 32 · 2019: 26 · 2018: 23 · 2017: 24 · 2016: 16 · 2015: 2
- FWCI
- 15.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Acta Neuropathologica (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health Grant (AG17586)
- the Marian S. Ware Alzheimer Program Cure Alzheimer’s Fund
- the Karen Cohen Segal and Christopher S. Segal Alzheimer Drug Discovery Initiative Fund
- the Paula C. Schmerler Fund for Alzheimer’s Research
- the Barrist Neurodegenerative Disease Research Fund
- the Eleanor Margaret Kurtz Endowed Fund
- the Mary Rasmus Endowed Fund for Alzheimer’s Research
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
- cell-to-cell transmission, locus coeruleus, PS19 mice, P301S tau, Alzheimer's disease, Braak hypothesis, tau tangles, efferent projections, axon terminals, neuronal perikarya, neurodegeneration
- MeSH terms
- Afferent Pathways, Animals, Disease Models, Animal, Efferent Pathways, Escherichia coli, Female, Humans, Hypothalamus, Immunohistochemistry, Locus Coeruleus, Male, Mice, Transgenic, Mutation, Neurons, Thalamus, Tyrosine 3-Monooxygenase, tau Proteins, Disease Progression, Tauopathies
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