Fig 2: MVC abrogated HIV-induced increased Tau phosphorylation. Levels of pTau (Thr181) (a, c, e, f) and total Tau (b, d, e) proteins in the hippocampus fimbria of each brain sample were analyzed by immunohistochemistry (a, b) followed by densitometry quantification (c, d), as well as by Western blot (e) followed by densitometry quantification normalized to sample’s total Tau levels (f). Levels of pTau (Ser396) (g, h), pTau (Ser199) (g, i), pTau (Thr231) (g, j), and pTau (Thr205) (g, k) were also quantified by Western blot (g) followed by densitometry quantification normalized to sample’s total Tau levels (h-k). For panels a and b, images were at 40X. The four animal groups analyzed included PBS, HIV, HIV + MVC, and MVC; 9 to 11 animals in each group. #P < 0.0001, **P = 0.002, *[(f) P = 0.011, (j) P = 0.048]. Error bars represent SD

Fig 3: Dysfunctional VSMCs induce Tau hyperphosphorylation and an in silico analysis of mutant Tau proteins(A) Representative western blots shows levels of total Tau (t-Tau) and multiple phosphorylate Tau residues (p-tau-Y18, p-tau-S262, p-tau-T205) from total lysates of VSMCs under AD-like conditions. CFL-1 (Coflin-1, a proliferative marker of VSMC). VCL was used as loading internal control.(B and C) In silico analysis of the WT and mutant TauP301L proteins.(D) Plot of distance (nm) vs time of the Y18 residue and R2-R3 domains after 500 ns of molecular dynamics simulations (MDSs) shows a significant reduction between the Y18 residue and the L301 mutant residue.

Fig 4: Effects of PA on behavioral impairments, C/EBPβ/AEP signaling pathway and AD-like pathologies after the overexpression of C/EBPβ in the hippocampus of TgCRND8 mice. A Schematic representation of the AAV genome encoding the CEBP/β sequence under the control of the CMV promoter; B experimental design and treatment schedule for identifying the potential mechanisms underlying the effects of PA on the TgCRND8 mice; C–L effects of PA (50 mg/kg) on behavioral impairments and cognitive deficits after the overexpression of C/EBPβ in the hippocampus of TgCRND8 mice (n = 8). C Representative images of the movement paths in OFT; D movement velocity in OFT; E distance traveled in OFT; F time spent in the center zone in OFT; G Recognition Index in NORT; H representative images of the swimming paths of mice in the MWMT probe test; I escape latency to platform during training days in MWMT; J numbers of the target crossing in the MWMT probe test; K the time spent in the target quadrant in the MWMT probe test; L swimming speed in the target quadrant in the MWMT probe test; M representative western blotting images and quantitative analysis of the protein expressions of C/EBPβ and AEP in the hippocampus (n = 3); N representative western blotting images and quantitative analysis of the protein expressions of hyperphosphorylated tau and Tau N368 in the hippocampus (n = 3); O Aβ40 and Aβ42 levels and Aβ42/Aβ40 ratio (n = 5). Data were expressed as the mean ± SEM (n = 3–8). #p < 0.05, ##p < 0.01 and ###p < 0.001 compared with the WT + OE-Control group; *p < 0.05, **p < 0.01 and ***p < 0.001 compared with the Tg + OE-Control group; ▲p < 0.05, ▲▲p < 0.01 and ▲▲▲▲p < 0.0001 compared with the Tg + OE-C/EBPβ group

Fig 5: Age-dependent accumulation of Tau and Cd68 protein in brain arterioles of the 3xtg-AD and 5xFAD transgenic mice(A and B) Immunofluorescence staining of coronal sections (8-μm thickness) of the mid-brain from wild-type (n = 4), 3xTg-AD (n = 4), and 5xFAD mice at 13, 27, and 44 wks of age. (A) shows staining of Tau (red) and Sm22α (green) in posterior inferior cerebral arteries (PICA) at 63 X magnification. (B) shows staining of Cd68 (magenta) and Sm22α (green) in posterior inferior cerebral arteries (PICA) at 63 X magnification. (Two slides per brain, mean ± SEM, p < 0.0001) in the PICA artery. Respectively, compared to the corresponding control, it is determined by one-way ANOVA. Scale bars: 80 μm.