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Dietary salt promotes cognitive impairment through tau phosphorylation.

TitleDietary salt promotes cognitive impairment through tau phosphorylation.
Publication TypeJournal Article
Year of Publication2019
AuthorsFaraco G, Hochrainer K, Segarra SG, Schaeffer S, Santisteban MM, Menon A, Jiang H, Holtzman DM, Anrather J, Iadecola C
JournalNature
Date Published2019 Oct 23
ISSN1476-4687
Abstract

Dietary habits and vascular risk factors promote both Alzheimer's disease and cognitive impairment caused by vascular factors. Furthermore, accumulation of hyperphosphorylated tau, a microtubule-associated protein and a hallmark of Alzheimer's pathology, is also linked to vascular cognitive impairment. In mice, a salt-rich diet leads to cognitive dysfunction associated with a nitric oxide deficit in cerebral endothelial cells and cerebral hypoperfusion. 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 kinaseĀ 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.

DOI10.1038/s41586-019-1688-z
Alternate JournalNature
PubMed ID31645758