Alzheimer brain-derived tau oligomers propagate pathology from endogenous tau
Open accessAbstract
Intracerebral injection of brain extracts containing amyloid or tau aggregates in transgenic animals can induce cerebral amyloidosis and tau pathology. We extracted pure populations of tau oligomers directly from the cerebral cortex of Alzheimer disease (AD) brain. These oligomers are potent inhibitors of long term potentiation (LTP) in hippocampal brain slices and disrupt memory in wild type mice. We observed for the first time that these authentic brain-derived tau oligomers propagate abnormal tau conformation of endogenous murine tau after prolonged incubation. The conformation and hydrophobicity of tau oligomers play a critical role in the initiation and spread of tau pathology in the naïve host in a manner reminiscent of sporadic AD.
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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 [50]
The Results sections on hippocampal long-term potentiation and pathological effects in vivo report impaired synaptic plasticity in brain slices and disrupted memory in mice after exposure to tau oligomers isolated from AD brains. These experiments support the proposed toxicity, but they do not establish that tau oligomers are the agents responsible for synaptic dysfunction or that they drive cognitive decline in people with AD. (LLM, conf=0.86)
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 [50]
The Results (Brain-derived tau oligomers seeding and toxicity in vitro) report oligomers forming before detectable fibrils, and the isolation results describe brain-derived oligomers without paired helical filament contamination. These findings support oligomers as distinct from fibrillar tau, but do not establish that they form prior to NFTs in AD brains or independently of NFT formation in vivo. (LLM, conf=0.82)
Experimental — accuracy not yet measuredOnce internalized, misfolded tau proteins act as a seed that recruits soluble endogenous tau into growing aggregates.
“Once internalized, misfolded tau proteins act as a seed that recruits soluble endogenous tau into growing aggregates11.”
From Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs) (2018) · cites this paper as [11]
Neurons can extracellularly release TauO, which serve as seeds that promote spreading and propagation of tau pathology in a prion-like fashion and induce cognitive deficits.
“Neurons can extracellularly release TauO, which serve as “seeds” that promote spreading and propagation of tau pathology in a prion‐like fashion and induce cognitive deficits. 11 , 12 , 13”
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 [11]
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 [11]
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“Therefore, we believe that some kind of soluble but toxic forms of tau oligomers or smaller aggregates may be responsible for neuronal cell death [49], such as cis p-Tau, disrupting microtubule networks and propagating to nearby neurons [50].”
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“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].”
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- Authors
- Lasagna-Reeves, C. A., Castillo-Carranza, D. L., Sengupta, U., Guerrero-Munoz, M. J., Kiritoshi, T., Neugebauer, V., Jackson, G. R., & Kayed, R.
- Affiliations
- The University of Texas Medical Branch at Galveston (US)
- Corresponding author
- Kayed, Rakez
- Venue
- Scientific Reports
- Published
- 2012-10-03
- Volume
- 2
- Issue
- 1
- Pages
- 700-700
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC3463004
- OpenAlex
- W2051532765
- Cited by
- 502
- References
- 57
- Citations by year
- 2026: 26 · 2025: 34 · 2024: 46 · 2023: 34 · 2022: 28 · 2021: 33 · 2020: 51 · 2019: 42 · 2018: 38 · 2017: 41 · 2016: 34 · 2015: 32 · 2014: 38 · 2013: 23 · 2012: 1
- FWCI
- 20.15
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Scientific Reports (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- Michael J. Fox Foundation for Parkinson's Research
- 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, Alzheimer's disease, tau conformation, long-term potentiation, hippocampus, memory impairment, cerebral cortex, amyloid, transgenic mice, hydrophobicity, sporadic Alzheimer's disease
- MeSH terms
- Alzheimer Disease, Animals, Cerebral Cortex, Hippocampus, Humans, Injections, Intraventricular, Memory, Mice, Transgenic, Neurons, Protein Conformation, Recombinant Proteins, Solutions, tau Proteins, Long-Term Potentiation, Excitatory Postsynaptic Potentials, Mice, Protein Multimerization, Hydrophobic and Hydrophilic Interactions
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