Soluble tau Species, Not Neurofibrillary Aggregates, Disrupt Neural System Integration in a tau Transgenic Model
Open accessAbstract
Neurofibrillary tangles are a feature of Alzheimer disease and other tauopathies, and although they are generally believed to be markers of neuronal pathology, there is little evidence evaluating whether tangles directly impact neuronal function. To investigate the response of cells in hippocampal circuits to complex behavioral stimuli, we used an environmental enrichment paradigm to induce expression of an immediate-early gene, Arc, in the rTg4510 mouse model of tauopathy. These mice reversibly overexpress P301L tau and exhibit substantial neurofibrillary tangle deposition, neuronal loss, and memory deficits. Using fluorescent in situ hybridization to detect Arc messenger RNA, we found that rTg4510 mice have impaired hippocampal Arc expression both without stimulation and in response to environmental enrichment; this likely reflects the combination of functional impairments of existing neurons and loss of neurons. However, tangle-bearing cells were at least as likely as non-tangle-bearing neurons to exhibit Arc expression in response to enrichment. Transgene suppression with doxycycline for 6 weeks resulted in increased percentages of Arc-positive cells in rTg4510 brains compared with untreated transgenics, restoring enrichment-induced Arc messenger RNA levels to that of wild-type controls despite the continued presence of neurofibrillary pathology. We interpret these data to indicate that soluble tau contributes to impairment of hippocampal function, although tangles do not preclude neurons from responding in a functional circuit.
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Tau oligomers are the toxic agents responsible for synaptic dysfunction in AD and drive cognitive decline.
“Several groups have demonstrated that tau oligomers, which form prior to and independent of NFTs, are the toxic agents responsible for synaptic dysfunction in AD and drive cognitive decline [26, 49, 50, 58, 95].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [26]
The Discussion (page not provided) reports that suppressing soluble tau expression rescued impaired hippocampal circuitry in a tau-transgenic mouse model despite persistent neurofibrillary pathology. The Introduction links soluble tau to memory impairment in those mice, but the paper does not identify tau oligomers as the toxic species or demonstrate that they cause synaptic dysfunction and cognitive decline in people with Alzheimer disease. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTau oligomers form prior to and independent of NFTs.
“Several groups have demonstrated that tau oligomers, which form prior to and independent of NFTs, are the toxic agents responsible for synaptic dysfunction in AD and drive cognitive decline [26, 49, 50, 58, 95].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [26]
The Discussion reports that reducing a soluble tau species improved Arc responses despite persistent neurofibrillary pathology. It does not identify that species as tau oligomers or say when oligomers form relative to NFTs; searches for tau oligomers and formation before tangles found no such passage in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measuredSoluble oligomeric tau may play a more essential role in neurodegeneration than insoluble fibrillar tau, including NFTs.
“These findings indicate that soluble oligomeric tau may play a more essential role in neurodegeneration than insoluble fibrillar tau (including NFT), the “tau we can see”.”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [27]
Soluble tau, rather than fibrillar tau, impacts responsiveness of neurons to environmental stimuli in hippocampus after memory formation.
“From assessments of immediate early gene expression in the hippocampus after memory formation, it again appears that soluble tau, rather than fibrillar tau, seems to impact the responsiveness of neurons to environmental stimuli.”
From All the Tau We Cannot See (2023) · cites this paper as [19]
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- Authors
- Fox, L. M., William, C. M., Adamowicz, D. H., Pitstick, R., Carlson, G. A., Spires-Jones, T. L., & Hyman, B. T.
- Affiliations
- Harvard University (US)
- Corresponding author
- Hyman, Bradley T.
- Venue
- Journal of Neuropathology & Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-07
- Volume
- 70
- Issue
- 7
- Pages
- 588-595
- ISSN
- 0022-3069 (ISSN-L)
- 1554-6578
- PMC
- PMC3118928
- OpenAlex
- W2132315817
- Cited by
- 88
- References
- 31
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 7 · 2023: 8 · 2022: 4 · 2021: 1 · 2020: 6 · 2019: 6 · 2018: 7 · 2017: 4 · 2016: 3 · 2015: 6 · 2014: 5 · 2013: 9 · 2012: 12
- FWCI
- 6.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Alzheimer's Association
- National Institutes of Health (K99AG33670, AG08487, AG026249)
- National Institute on Aging (AG-08487, R01AG026249, R01AG008487, AG026249, K99AG33670, P50AG005134, K99AG033670, P30AG062421)
- National Institute of Neurological Disorders and Stroke (K08NS069811)
- 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
- soluble tau, neurofibrillary tangles, tauopathy, Alzheimer's disease, P301L tau, Arc, environmental enrichment, hippocampal circuitry, neural integration, neurofibrillary pathology
- MeSH terms
- Animals, Cell Count, Cytoskeletal Proteins, Disease Models, Animal, Doxycycline, Environment, Gene Expression Regulation, Hippocampus, Indoles, Leucine, Mutation, Nerve Tissue Proteins, Neurons, Proline, RNA, Messenger, Neurofibrillary Tangles, tau Proteins, Tauopathies, Animals, Genetically Modified, Mice
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