Pathological tau promotes neuronal damage by impairing ribosomal function and decreasing protein synthesis
Open accessAbstract
One of the most common symptoms of Alzheimer's disease (AD) and related tauopathies is memory loss. The exact mechanisms leading to memory loss in tauopathies are not yet known; however, decreased translation due to ribosomal dysfunction has been implicated as a part of this process. Here we use a proteomics approach that incorporates subcellular fractionation and coimmunoprecipitation of tau from human AD and non-demented control brains to identify novel interactions between tau and the endoplasmic reticulum (ER). We show that ribosomes associate more closely with tau in AD than with tau in control brains, and that this abnormal association leads to a decrease in RNA translation. The aberrant tau-ribosome association also impaired synthesis of the synaptic protein PSD-95, suggesting that this phenomenon contributes to synaptic dysfunction. These findings provide novel information about tau-protein interactions in human brains, and they describe, for the first time, a dysfunctional consequence of tau-ribosome associations that directly alters protein synthesis. Significance statement: Despite the identification of abnormal tau-ribosomal interactions in tauopathies >25 years ago, the consequences of this association remained elusive until now. Here, we show that pathological tau associates closely with ribosomes in AD brains, and that this interaction impairs protein synthesis. The overall result is a stark reduction of nascent proteins, including those that participate in synaptic plasticity, which is crucial for learning and memory. These data mechanistically link a common pathologic sign, such as the appearance of pathological tau inside brain cells, with cognitive impairments evident in virtually all tauopathies.
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m6A accumulates in the cytoplasm in response to stress.
“m6A is known to accumulate in the cytoplasm in response to stress, but the function of cytoplasmic m6A remains to be clearly delineated (Meier et al., 2016; Briggs et al., 2017; Koren et al., 2019; Ries et al., 2019; Wolozin and Ivanov, 2019; Fu and Zhuang, 2020).”
From β-amyloid accumulation enhances microtubule associated protein tau pathology in an APPNL-G-F/MAPTP301S mouse model of Alzheimer’s disease (2024) · cites this paper as Meier et al., 2016
The Results passages describe pathological tau associating with ribosomes and reducing protein synthesis, not m6A localization. Searches for m6A, N6-methyladenosine, and cytoplasmic accumulation under stress found no passage addressing the claim in our copy. (LLM, conf=0.74)
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- Authors
- Meier, S., Bell, M., Lyons, D. N., Rodriguez-Rivera, J., Ingram, A., Fontaine, S. N., Mechas, E., Chen, J., Wolozin, B., LeVine, H., Zhu, H., & Abisambra, J. F.
- Affiliations
- Boston University (US)
- University of Kentucky (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2016-01-20
- Volume
- 36
- Issue
- 3
- Pages
- 1001-1007
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4719006
- OpenAlex
- W2287813183
- Cited by
- 190
- References
- 35
- Citations by year
- 2026: 19 · 2025: 20 · 2024: 13 · 2023: 16 · 2022: 23 · 2021: 28 · 2020: 24 · 2019: 23 · 2018: 8 · 2017: 11 · 2016: 5
- FWCI
- 12.62
- 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)
- UKnowledge (University of Kentucky) (submittedVersion, cc-by)
- Funders
- U.S. Department of Defense (AZ140097)
- Alzheimer's Association (NIRG-14-322441)
- GlaxoSmithKline
- University of Kentucky (P30 AG028383, AG028383, P30 CA177558)
- National Institutes of Health (AG028 383, NIH/NIMHD L32 MD009205-01, UL1TR000117, L32 MD009205-01, NIH/NINDS 1R01 NS091329-01)
- National Institute on Aging (AG-028383, P30AG028383, NIA P30 AG028383, NIH/NIA P30 AG028383)
- National Cancer Institute (P30CA177558)
- National Institute of General Medical Sciences (P30GM110787, P20GM103486)
- National Institute of Neurological Disorders and Stroke (NS091329, R01NS091329, R01NS077284, P30NS051220)
- National Center for Research Resources (S10RR029127)
- National Center for Advancing Translational Sciences
- National Institute on Minority Health and Health Disparities (L32MD009205-01, L32 MD009205)
- 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
- pathological tau, Alzheimer's disease, tauopathy, protein synthesis, endoplasmic reticulum, PSD-95, synaptic dysfunction, memory loss, synaptic plasticity
- MeSH terms
- Aged, 80 and over, Alzheimer Disease, Brain, Cells, Cultured, Female, Humans, Male, Microsomes, Neurons, Ribosomes, Protein Biosynthesis, tau Proteins, Tauopathies
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