Fig. 5: Recombinant IL33 (rIL33) enhances drainage of intracerebroventricularly (ICV) injected peptide, but has limited effect on reduction of neuronal PHF1 tau in Il33^−/− mice.

a Immunohistochemistry shows neuronal PHF1 in indicated groups; note slightly reduced PHF1 in Il33^−/−+rIL33 mice as compared with Il33^−/−+PBS controls; no PHF1 was detectable in WT mice. Bars’ unit = μm b Regression analysis shows no linear correlation between total cortical AQP4 level (% of area) vs neuronal PHF1 among Il33^−/−+PBS, Il33^−/−+IL33, and WT mice; note that total AQP4 level in Il33^−/−+IL33 mice is not proportional to neuronal PHF1. Neuronal PHF1 was quantitated on digital immunostaining imagines, and expressed as IOD/neurons. c Statistical analysis shows a linear negative regression (black dotted line) between cortical and glomerular PHF1 among WT, Il33^−/−+PBS and Il33^−/−+rIL33 mice at 70 weeks; three mice were used for each group. d ELISA shows a sixfold increase in serum pCol peptide that had been injected into ventricles 24 h ago in Il33^−/−+rIL33 mice, as compared to PBS controls. e Diagram depicts two aqueous flows driven by astrocyte AQP4 (lightly colored arrows): Flow 1, driven by n-AQP4, brings neuronal wastes away from neurons, and Flow 2, convective flow driven by p-AQP4 toward perivenous space, flushes brain wastes further to perivenous space, i.e., glymphatics. Therefore, a lack of n-AQP4 results in ineffective removal of neuronal wastes, e.g., PHF1 from neurons.