Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice
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Background: The correlation between neurofibrillary tangles of tau and disease progression in the brains of Alzheimer's disease (AD) patients remains an area of contention. Innovative data are emerging from biochemical, cell-based and transgenic mouse studies that suggest that tau oligomers, a pre-filament form of tau, may be the most toxic and pathologically significant tau aggregate. Results: Here we report that oligomers of recombinant full-length human tau protein are neurotoxic in vivo after subcortical stereotaxic injection into mice. Tau oligomers impaired memory consolidation, whereas tau fibrils and monomers did not. Additionally, tau oligomers induced synaptic dysfunction by reducing the levels of synaptic vesicle-associated proteins synaptophysin and septin-11. Tau oligomers produced mitochondrial dysfunction by decreasing the levels of NADH-ubiquinone oxidoreductase (electron transport chain complex I), and activated caspase-9, which is related to the apoptotic mitochondrial pathway. Conclusions: This study identifies tau oligomers as an acutely toxic tau species in vivo, and suggests that tau oligomers induce neurodegeneration by affecting mitochondrial and synaptic function, both of which are early hallmarks in AD and other tauopathies. These results open new avenues for neuroprotective intervention strategies of tauopathies by targeting tau oligomers.
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Smaller, soluble tau oligomers (TauO), not neurofibrillary tangles (NFTs), are the most toxic tau species.
“our laboratory and others found that smaller, soluble tau oligomers (TauO) —not NFTs—are the most toxic tau species. 9 , 10 , 11”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [10]
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Taddei, R. N., Perbet, R., Mate de Gerando, A., Wiedmer, A. E., Sanchez-Mico, M., Connors Stewart, T., Gaona, A., Melloni, A., Amaral, A. C., Duff, K., et al. (2023) · JAMA Neurology · doi:10.1001/jamaneurol.2023.3530 · Cited by 110 · see citing works
Lorenzo, F. D., Ponzo, V., Bonnı̀, S., Motta, C., Serra, P. C. N., Bozzali, M., Caltagirone, C., Martorana, A., & Koch, G. (2016) · Annals of Neurology · doi:10.1002/ana.24695 · Cited by 110 · see citing works
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Holper, S., Watson, R., & Yassi, N. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23137307 · Cited by 114 · see citing works
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- Authors
- Lasagna-Reeves, C. A., Castillo-Carranza, D. L., Sengupta, U., Clos, A. L., Jackson, G. R., & Kayed, R.
- Affiliations
- The University of Texas Medical Branch at Galveston (US)
- Corresponding author
- Kayed, Rakez
- Venue
- Molecular Neurodegeneration
- Published
- 2011-06-06
- Volume
- 6
- Issue
- 1
- Pages
- 39-39
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC3224595
- OpenAlex
- W1968276382
- Cited by
- 633
- References
- 84
- Citations by year
- 2026: 52 · 2025: 67 · 2024: 46 · 2023: 53 · 2022: 52 · 2021: 51 · 2020: 57 · 2019: 43 · 2018: 44 · 2017: 35 · 2016: 27 · 2015: 33 · 2014: 27 · 2013: 28 · 2012: 12
- FWCI
- 15.93
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Alzheimer's Drug Discovery Foundation
- Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch
- 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 oligomers, tauopathy, Alzheimer's disease, neurotoxicity, memory consolidation, synaptic dysfunction, synaptophysin, mitochondrial dysfunction, complex I, caspase-9, apoptosis, neurofibrillary tangles, stereotactic injection, neurodegeneration
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