Fig 2: Schematic illustration of the mechanism for p-Tau to mediate METH-induced podocyte pathology. Upon METH treatment, the activated GSK3ß (phosphorylated GSK3ß) could lead to Tau phosphorylation. The phosphorylated Tau may trigger podocyte pathology including podocyte simplification, foot process effacement, and podocyte specific protein loss. Inhibiting GSK3ß activation by LiCl could alleviate the podocyte injury induced by METH. The luteolin could prevent the podocyte pathology, and it might be p-Tau dependent.

Fig 3: STZ leads to increased tau phosphorylation in frontal cortex (including ACC) and hippocampus.a, b Tau levels at Ser396 were significantly elevated in the hippocampus (a) and frontal cortex (b). Proportions of pTau396 normalized to total tau are on the y-axes. Dots show individual data points (see “Methods”). Saline control values are in gray and STZ in magenta. Representative western blot images are shown in the insets. *p < 0.05; ***p < 0.001. Error bars = SEM.

Fig 4: Effect of rTMS on the activities of GSK-3ß, Tau, and ß-catenin in AD mice. AD symptoms were induced with intracranial injection of 3 µl Aß1-42 (1 µg/µl) and then treated with rTMS of 1 Hz or 10 Hz. The activities of GSK-3ß, Tau, and ß-catenin were detected with western blotting assay. “*” represents statistically significant different from Sham group, P < 0.05. “#” represents statistically significant different from AD group, P < 0.05. Each assay was represented by six replicates.

Fig 5: A theoretical model for pathological tau phosphorylation and progression in CCD. A. Tau is physiologically found primarily in the axon, where it stabilizes microtubules, as well as in dendrites. B. Tau becomes hyperphosphorylated at the S396 residue in the axon, dendrites and axon terminals, and begins accumulating. C. P-tau mis-localizes to soma where it begins to accumulate further, likely as a precursor to neurofibrillary pathology. D. Mis-localized, misfolded hyperphosphorylated tau in the soma forms fibrillary structures such as paired helical filaments and becomes an AT8+ neurofibrillary tangle. E. Schema for the Papez Circuit as examined in the present study, overlaid on a human brain. Neurons in CCD brains within this circuit and related brain regions were observed to be at various stages of tau dysfunction illustrated in B–D.