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Cited by 236Alzheimer's disease research and treatmentsNeurological Disease Mechanisms and TreatmentsDementia and Cognitive Impairment Research

Dietary salt promotes cognitive impairment through tau phosphorylation

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Faraco, Giuseppe, Hochrainer, Karin, Segarra, Steven G., Schaeffer, Samantha, Santisteban, Monica M., Menon, Ajay, Jiang, Hong, Holtzman, David M. +2 more·2019·Nature
DOI 10.1038/s41586-019-1688-zPMC PMC7380655

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Abstract

Dietary habits and vascular risk factors promote both Alzheimer's disease and cognitive impairment caused by vascular factors 1-3. Furthermore, accumulation of hyperphosphorylated tau, a microtubule-associated protein and a hallmark of Alzheimer's pathology 4, is also linked to vascular cognitive impairment 5,6. In mice, a salt-rich diet leads to cognitive dysfunction associated with a nitric oxide deficit in cerebral endothelial cells and cerebral hypoperfusion 7. Here we report that dietary salt induces hyperphosphorylation of tau followed by cognitive dysfunction in mice, and that these effects are prevented by restoring endothelial nitric oxide production. The nitric oxide deficiency reduces neuronal calpain nitrosylation and results in enzyme activation, which, in turn, leads to tau phosphorylation by activating cyclin-dependent kinase 5. Salt-induced cognitive impairment is not observed in tau-null mice or in mice treated with anti-tau antibodies, despite persistent cerebral hypoperfusion and neurovascular dysfunction. These findings identify a causal link between dietary salt, endothelial dysfunction and tau pathology, independent of haemodynamic insufficiency. Avoidance of excessive salt intake and maintenance of vascular health may help to stave off the vascular and neurodegenerative pathologies that underlie dementia in the elderly.

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  • In a vascular injury model induced by high-salt diet, tau ablation rescued molecular pathways underlying neurovascular dysfunction.

    “In a vascular injury model induced by high-salt diet, tau ablation rescued molecular pathways underlying neurovascular dysfunction [87].”

    From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [87]

    The tau-null experiment (passage [6]) reports that high-salt-fed mice avoided cognitive impairment but still had an attenuated cerebral blood-flow response, a measure of neurovascular dysfunction. The Abstract (passage [2]) likewise says cognitive impairment was absent despite persistent hypoperfusion and neurovascular dysfunction. Tau ablation therefore rescued cognition, not the neurovascular dysfunction attributed to it in the claim. (LLM, conf=0.92)

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  • Tau ablation improves outcomes in models of TBI and high-salt diet-induced vascular dysfunction, with improvements in cognitive performance.

    “Beyond neurodegenerative and neurodevelopmental disorders, tau ablation has also been shown to improve outcomes in models of neurological injury and vascular stress, such TBI and high-salt diet-induced vascular dysfunction, with associated improvements in cognitive performance [72, 86, 87].”

    From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [87]

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Authors
Faraco, G., Hochrainer, K., Segarra, S. G., Schaeffer, S., Santisteban, M. M., Menon, A., Jiang, H., Holtzman, D. M., Anrather, J., & Iadecola, C.
Affiliations
  • Weill Cornell Medicine (US)
  • Washington University in St. Louis (US)
Corresponding author
  • Faraco, Giuseppe
  • Iadecola, Costantino
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2019-10-23
Volume
574
Issue
7780
Pages
686-690
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-019-1688-z
PMC
PMC7380655
OpenAlex
W2981842151
Cited by
236
References
10
Citations by year
2026: 29 · 2025: 41 · 2024: 35 · 2023: 29 · 2022: 42 · 2021: 33 · 2020: 23 · 2019: 4
FWCI
17.49
Type
journal article
Language
en
Update notices
correction (2020-01-14)
Open access
Licence
Locations
  • Nature (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • American Heart Association
  • Cure Alzheimer's Fund
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (R01NS109588, R37NS089323, R01NS095441)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
dietary salt, hyperphosphorylated tau, cognitive impairment, vascular cognitive impairment, Alzheimer's disease, endothelial nitric oxide, cyclin-dependent kinase 5, cerebral hypoperfusion, neurovascular dysfunction, endothelial dysfunction
MeSH terms
Alzheimer Disease, Animals, Brain, Humans, Neurons, Phosphorylation, tau Proteins, Sodium Chloride, Dietary, Mice, Knockout, Mice, Cognitive Dysfunction

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