Fig. 9. Direct and indirect pathways mediating neuronal toxicity of Tau.

a Immunohistochemistry of Tau-injected mice revealed most of the non-microglia cells incorporating tau were MAP2-positive neurons but not GFAP-positive astrocytes. The ratios of Tau-incorporating cells were equivalent in non-induced and tamoxifen-induced Pqbp1-cKO mice, as the basis for analyses in (b). N = 20 images from three mice. Statistical test: Student’s t-test. b Frequencies of neuronal cell death (TUNEL-positive and NeuN-positive dying neurons) by addition of normal or PQBP1-binding mutant Tau 410 were changed in Tau-negative neurons in addition to that of Tau-positive neurons. Indirect effect of Tau 410 monomer on Tau-negative neurons was suppressed by PQBP1-binding mutation or by tamoxifen-induced Pqbp1-cKO, while the direct effect of Tau 410 polymers on Tau-positive neurons was not affected by PQBP1-binding mutation or by tamoxifen-induced Pqbp1-cKO. TUNEL terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Values in each group are presented as mean ± SEM. N = 4 fields. ^#P < 0.05, ^##P < 0.01 in Tukey’s HSD test. c Direct effect of monomer and polymerized Tau 410 on primary neurons. Non-polymerized Tau 410 was not toxic to neurons in the absence of microglia. N = 5 visual fields. ^n.s.P > 0.05 in Tukey’s HSD test. d Direct and indirect pathways from extracellular tau to neuronal damage. Tau polymer directly damages neurons, while tau monomer is incorporated into LPL-negative non-DAM microglia (Supplementary Fig. 8), and indirectly damages neurons via cytokines. Though not included in this study, DAM around Aβ plaques might play a different role to prevent tau seeding. Box plots show the median, quartiles, and whiskers that represent data outside the 25th to 75th percentile range.