Duration of tau hyperphosphorylation and spatial memory deficit induced by single injection of Forskolin into lateral ventricle of rat / 中国医学科学院学报

<p><b>OBJECTIVE</b>To investigate the duration of tau hyperphosphorylation and spatial memory retentive deficit induced by single injecting with Forskolin, a protein kinase A activator, into lateral ventricle of rats, and the correlation between the two pathological alterations.</p><p><b>METHODS</b>Forskolin (80 micromol/L, 40 microl) was injected into the lateral ventricle by stereotaxic injection. Tau phosphorylation and spatial memory retention were measured by Western blot/immunocytochemistry and Morris-Water-Maze test, respectively.</p><p><b>RESULTS</b>The phosphorylation levels of tau at Tau-1, PHF-1, and pS214 epitopes were significantly elevated at 24, 48 and 72 h after single administration of Forskolin (P < 0.05). The most significant elevation was seen at 48 h (P < 0.01) and it tended to recover at 72 h (P < 0.05) after injection. The correlation between the two pathological alterations was positive at PHF-1 site (r = 0.97, P < 0.05), negative at Tau-1 site (r = -0.963, P < 0.05), and not significant at pS214 site (r = 0.705, P > 0.05).</p><p><b>CONCLUSIONS</b>Forskolin can induce tau hyperphosphorylation and spatial memory retentive deficit within a certain period of time. The level of tau phosphorylation in hippocampus is somehow correlated with the spatial memory deficit in rats.</p>

Inhibition of melatonin biosynthesis activates protein kinase a and induces Alzheimer-like tau hyperphosphorylation in rats / 中国医学科学杂志(英文版)

<p><b>OBJECTIVE</b>To investigate effect of inhibiting melatonin biosynthesis on activities of protein kinase A (PKA), glycogen synthase kinase-3 (GSK-3) and tau phosphorylation at PS214 and M4 epitopes using haloperidol, a specific inhibitor of 5-hydroxyindole-O-methyltransferase.</p><p><b>METHODS</b>Brain ventricular and intraperitoneal injections were used for haloperidol administration, Western blots for tau phosphorylation, 32P-labeling for PKA and GSK-3 activity, and high performance liquid chromatograph for detection of serum melatonin levels.</p><p><b>RESULTS</b>Haloperidol injection through the lateral ventricle and intraperitoneal reinforcement significantly stimulated PKA activity with a concurrent hyperphosphorylation of tau at M4 (Thr231/Ser235) and PS214 (Ser214) sites. Prior treatment of the rats using melatonin supplement for one week and reinforcement during the haloperidol administration arrested PKA activity and attenuated tau hyperphosphorylation. GSK-3 activity showed no obvious change after haloperidol injection, however, melatonin supplements and reinforcements during haloperidol infusion inactivated basal activity of GSK-3.</p><p><b>CONCLUSION</b>Decreased melatonin may be involved in Alzheimer-like tau hyperphosphorylation, and overactivation of PKA may play a crucial role in this process.</p>