Abstract
Background: Although there are numerous investigations regarding the beneficial effects of exercise rehabilitation (ER) or astragaloside (AST) after amyloid-beta (Ab) pathology, the mechanisms are still not well understood. We aim to assess whether ER and/or AST counteract Ab pathology via diminishing brain-derived neurotrophic factor (BDNF) signaling deficits and mitochondrial dysfunction. Methods: Ab1-42 were microinjected into the bilateral ventricles to induce Ab neuropathology in rats. The Alzet osmotic pump containing full of AST was implanted subcutaneously during surgery. The ER group of rats started at seven days post-surgery and lasted for four weeks. The ANA12 was administrated once per day to the endpoint of the experiments to antagonize the BDNF action. Neurobehavioral functions were evaluated by Y-maze, radial maze, and rotarod tests one day before surgery and 14 to 35 days post-surgery. Cortical and hippocampal expressions of both BDNF/TrkB and cathepsin D were determined by Western blotting method. The rat primary cultured cortical neurons were incubated with BDNF and/or AST and ANA12 followed by exposure to aggregated Ab for 24 hours. The cell viability (by MTT assay), mitochondrial membrane permeability and electrochemical potential (by JC-1 stain), DNA fragmentation (sub-G1 and DNA ladder assay), synaptic plasticity (by immunofluorescence stain), and pTrkB/pAkt/pGSK3b/b-catenin signaling (by Western blot) were determined.Results: ER and/or AST reversed neurobehavioral disorders, downregulation of cortical and hippocampal expression of both BDNF/TrkB and cathepsin D, neural pathology, Ab accumulation, and altered microglial polarization caused by Ab. In vitro studies also confirmed that topical application of BDNF and/or AST reversed the Ab-induced cytotoxicity, apoptosis, mitochondrial distress, synaptotoxicity, and decreased expression of p-TrkB, AKT, p-GSK3b, and b-catenin in altered rat cortical neurons. In particular, the beneficial effects of combined ER (or BDNF) and AST therapy in vivo and in vitro were superior to ER (or BDNF) or AST alone. Furthermore, we observed that any gains from ER (or BDNF) and/or AST could be significantly eliminated by ANA-12, a potent BDNF/TrkB antagonist. Conclusion: These results indicate that whereas ER (or BDNF) and/or AST attenuate Ab pathology by reversing BDNF/TrkB signaling deficits and mitochondrial dysfunction. In particular, AST can be an alternative therapy to replace ER.
The carbonic anhydrase inhibitor methazolamide prevents amyloid beta-induced mitochondrial dysfunction and caspase activation protecting neuronal and glial cells in vitro and in the mouse brain