Original ArticlesPhosphorylation of Tau, Aβ-Formation, and Apoptosis After In Vivo Inhibition of PP-1 and PP-2A
Section snippets
Application of Okadaic Acid (OA)
Adult Wistar rats received infusions of OA (ammonium salt, Biotrend) into lateral ventricles at a dosage of 70 ng/day via mini-osmotic pumps [4](mean pumping rate: 0.51 ± 0.02 μL/h; alzet model 2002, ALZA Cooperation, Palo Alto). Infusion cannulae (0.36 mm diameter) were stereotaxically placed under anesthesia (15 mg/kg, i.m. Rompun, Bayer, Leverkusen; 100 mg/kg, i.m. Velonarcon, Berlin-Chemie AG) at the following co-ordinates (in mm from bregma and dura, flat skull): AP-0.9; L-1.4; V-3.8. OA
Results
Okadaic acid, a specific inhibitor of protein phosphatases 1 and 2A, was continuously infused into lateral ventricles of rat brain through mini-osmotic pumps for different periods of time up to 4 months. The sequelae of a continuous inhibition of PP-1 and 2A on the expression, subcellular distribution, and phosphorylation of tau and neurofilaments, on the expression and amyloidogenic processing of the amyloid precursor protein and on neuronal viability and the induction of apoptotic cell death
Discussion
The present study extends our previous observations that chronic infusion of okadaic acid into rat brain results in an increased phosphorylation and subcellular redistribution of cytoskeletal proteins, as well as alterations in the expression and processing of the amyloid precursor protein 3, 4. The results demonstrate, furthermore, that these pathological alterations develop in a certain topographical pattern and with a characteristic time course, and show a typical relationship to apoptotic
Acknowledgements
This study was supported by the Deutsche Forschungsgemeinschaft (Ar 200/2–2) and by the Bundesministerium für Bildung, Forschung und Technologie (BMBF), Interdisciplinary Center for Clinical Research at the University of Leipzig (IZKF-C1). We thank Dr. D. Taylor for linguistic revision.
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2013, European Journal of PharmacologyCitation Excerpt :Nowadays, a growing body of work supports the notion that Aβ regulates the phosphorylation of tau to accelerate NFT formation (Huang and Jiang, 2009; Zheng et al., 2002). Also the hyperphosphorylation tau protein increase accumulation of Aβ and decreases its degradation (Arendt et al., 1998; Desikan et al., 2012). In the present study, we found that i.c.v. OKA-injected increased Aβ expression, which was consistent with the previous report (Arendt et al., 1995; 1998).