We aim to investigate the mechanisms underlying the beneficial effects of
exercise rehabilitation (ER) and/or astragaloside (AST) in counteracting
amyloid-beta (Aβ) pathology. Aβ oligomers were microinjected into the bilateral ventricles to induce Aβ neuropathology in rats. Neurobehavioral functions were evaluated. Cortical and hippocampal expressions of both
BDNF/TrkB and
cathepsin D were determined by the western blotting method. The rat primary cultured cortical neurons were incubated with
BDNF and/or AST and ANA12 followed by exposure to aggregated Aβ for 24 h. In vivo results showed that ER and/or AST reversed neurobehavioral disorders, downregulation of cortical and hippocampal expression of both
BDNF/TrkB and
cathepsin D, neural pathology, Aβ accumulation, and altered microglial polarization caused by Aβ. In vitro studies also confirmed that topical application of
BDNF and/or AST reversed the Aβ-induced cytotoxicity, apoptosis, mitochondrial distress, and synaptotoxicity and decreased expression of p-TrkB, p-Akt, p-GSK3β, and β-
catenin in rat cortical neurons. 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. These results indicate that whereas ER (or
BDNF) and/or AST attenuate Aβ pathology by reversing
BDNF/TrkB signaling deficits and
mitochondrial dysfunction, combining these two potentiates each other's
therapeutic effects. In particular, AST can be an alternative
therapy to replace ER.