a, HSD has no effect on the expression or activity of GSK3β in the neocortex. ND/HSD n = 10/10. b, HSD does not alter the expression of the prolyl cis/trans isomerase PIN-1, a regulator of tau dephosphorylation. ND/HSD n = 5/5. c, The expression of calpastatin, an endogenous inhibitor of calpain activity, is not reduced by HSD. ND/HSD n = 10/10. d, Nitrosylation of CDK5 is reduced in the neocortex of HSD-fed mice (ND/HSD n = 9/9, diet: *P = 0.0143; ascorbate: *P < 0.0001; two-way ANOVA and Tukey’s test). e, HJ8.8 reduces AT8 in the hippocampus (IgG: ND/HSD n = 13/12; HJ8.8: ND/HSD n = 9/13; *P < 0.0001, Kruskal–Wallis test and Dunn’s test). RZ3 levels are not altered by HJ8.8. f, Administration of HJ8.8 does alter the increase in serum IL-17 levels induced by HSD (IgG: ND/HSD n = 9/9, *P = 0.0192 versus ND IgG; HJ8.8: ND/HSD n = 7/5, *P = 0.0421 versus ND HJ8.8, two-tailed unpaired t-test). g, The increase in somatosensory cortex CBF induced by neural activity evoked by mechanical stimulation of the whiskers is not reduced by HSD in wild-type, tau−/− or HJ8.8-treated mice (wild-type ND/HSD n = 5/7, tau−/− ND/HSD n = 9/8; IgG ND/HSD n = 5/5, HJ8.8 ND/HSD n = 5/5). h, Western blotting showing enrichment of tau in boiled RIPA neocortical samples (heat-stable fraction, HS). Note that β-actin is lost during the boiling process. Representative images from n = 3 experiments. i, Cartoon depicting the mechanisms by which HSD leads to tau phosphorylation and cognitive impairment. HSD elicits a T H 17 response in the small intestine, which leads to an increase in circulating IL-17. IL-17, in turn, suppresses endothelial NO production by inducing inhibitory phosphorylation of eNOS at Thr495. The NO deficit results in reduced nitrosylation of calpain in neurons, and increases in calpain activity, p35 to p25 cleavage, activation of CDK5, and tau phosphorylation, which is ultimately responsible for cognitive dysfunction. In support of this chain of events, rescuing the endothelial NO deficit with l-arginine, lack of tau in tau-null mice, treatment with the CDK5 peptide inhibitor TFP5 or treatment with antibodies directed against tau (Tau ab) prevent the cognitive dysfunction. For gel source data see Supplementary Fig. 1. Data are expressed as mean ± s.e.m. Source data