Tau aggregation and progressive neuronal degeneration in the absence of changes in spine density and morphology after targeted expression of Alzheimer's disease-relevant tau constructs in organotypic hippocampal slices
Open accessAbstract
Alzheimer's disease (AD) is characterized by progressive loss of neurons in selected brain regions, extracellular accumulations of amyloid β, and intracellular fibrils containing hyperphosphorylated tau. Tau mutations in familial tauopathies confirmed a central role of tau pathology; however, the role of tau alteration and the sequence of tau-dependent neurodegeneration in AD remain elusive. Using Sindbis virus-mediated expression of AD-relevant tau constructs in hippocampal slices, we show that disease-like tau modifications affect tau phosphorylation at selected sites, induce Alz50/MC1-reactive pathological tau conformation, cause accumulation of insoluble tau, and induce region-specific neurodegeneration. Live imaging demonstrates that tau-dependent degeneration is associated with the development of a “ballooned” phenotype, a distinct feature of cell death. Spine density and morphology is not altered as judged from algorithm-based evaluation of dendritic spines, suggesting that synaptic integrity is remarkably stable against tau-dependent degeneration. The data provide evidence that tau-induced cell death involves apoptotic as well as nonapoptotic mechanisms. Furthermore, they demonstrate that targeted expression of tau in hippocampal slices provides a novel model to analyze tau modification and spatiotemporal dynamics of tau-dependent neurodegeneration in an authentic CNS environment.
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Our findings in the hippocampus support in vitro studies showing that hyperphosphorylated tau does not induce spine loss in primary hippocampal neuron cultures or organotypic slices.
“Our findings in the hippocampus support in vitro studies showing that hyperphosphorylated tau does not induce spine loss in primary hippocampal neuron cultures or organotypic slices (Shahani et al., 2006, Hoover et al., 2010, Miller et al., 2014).”
From Dendritic Spine Remodeling and Synaptic Tau Levels in PS19 Tauopathy Mice (2021) · cites this paper as Shahani et al., 2006
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Cites
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Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease
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Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease
West, M. J., Coleman, P. D., Flood, D. G., & Troncoso, J. C. (1994) · The Lancet · doi:10.1016/s0140-6736(94)92338-8 · Cited by 1,267 · cited 1× · see citing works
“In AD and after hypoxic/ischemic insults, CA1 region typically demonstrates profound vulnerability to neuronal cell death (SchmidtKastner and Freund, 1991; West et al., 1994).”
BackgroundTau pathology in Alzheimer disease and other tauopathies
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Tau molecular diversity contributes to clinical heterogeneity in Alzheimer’s disease
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Soluble forms of tau are toxic in Alzheimer's disease
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Tau Oligomers: The Toxic Player at Synapses in Alzheimer’s Disease
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Dendritic Spines: Mediators of Cognitive Resilience in Aging and Alzheimer’s Disease
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Dendritic Spine Remodeling and Synaptic Tau Levels in PS19 Tauopathy Mice
Walker, C. K., Greathouse, K. M., Boros, B. D., Poovey, E. H., Clearman, K. R., Ramdas, R., Muhammad, H. M., & Herskowitz, J. H. (2021) · Neuroscience · doi:10.1016/j.neuroscience.2020.12.006 · Cited by 27 · see citing works
- Authors
- Shahani, N., Subramaniam, S., Wolf, T., Tackenberg, C., & Brandt, R.
- Affiliations
- Osnabrück University (DE)
- Heidelberg University (DE)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2006-05-31
- Volume
- 26
- Issue
- 22
- Pages
- 6103-6114
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6675219
- OpenAlex
- W2083337183
- Cited by
- 81
- References
- 7
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 2 · 2022: 3 · 2021: 1 · 2020: 7 · 2019: 3 · 2018: 5 · 2017: 5 · 2016: 8 · 2015: 3 · 2014: 2 · 2013: 3 · 2012: 7
- FWCI
- 5.27
- 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)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Niedersächsisches Ministerium für Wissenschaft und Kultur
- 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
- tau aggregation, Alzheimer's disease, tau phosphorylation, neurodegeneration, dendritic spines, synaptic integrity, cell death, apoptosis, non-apoptotic cell death, Sindbis virus, hippocampal slices
- MeSH terms
- Alzheimer Disease, Animals, Cell Line, Genetic Vectors, Cricetinae, Hippocampus, Humans, Organ Culture Techniques, tau Proteins, Genes, Reporter, Green Fluorescent Proteins, Mice
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