Dendrobium nobile Lindl. Alkaloids Ameliorate A beta(25-35)-Induced Synaptic Deficits by Targeting Wnt/beta-Catenin Pathway in Alzheimer's Disease Models

Background: Dendrobium nobile Lindl. alkaloids (DNLA) are effective in ameliorating cognitive deficit in SAMP8, A beta PP/PS1, and LPS-induced AD animal models, and prevented A beta-induced synaptic degeneration in cultured hippocampal neurons. However, the underlying mechanisms remain unexplored. Objective: This study investigated the protective effects of DNLA on synaptic damage in an A beta(25-35)-induced rat AD model, in primary cortical neuron cultures, and in PC12 cells transfected with human A beta PP695, focusing on the Wnt/beta-catenin pathway. Methods: Sprague-Dawley rats received a single A beta(25-35) injection (10 mu g) into the bilateral hippocampi. DNLA (40 and 80 mg/kg/d) was intragastrically administrated 7 days prior to A beta injection and continued for 28 days. The spatial learning and memory, synaptic morphology, synapse-related proteins, and Wnt signaling components GSK3 beta and beta-catenin phosphorylation were evaluated. Rat primary cortical neuron cultures and A beta PP695-PC12 cells were used to evaluate axonal mitochondria distribution, reactive oxygen species production, amyloidogenesis, and Wnt pathway in the protection. Results: DNLA ameliorated A beta-induced cognitive impairment, increased the number of synapses, elevated the postsynaptic density thickness and expression of synapsin and PSD95 in the hippocampus, and suppressed A beta-mediated GSK3 beta activity and the beta-catenin phosphorylation. In primary neurons and A beta PP695-PC12 cells, DNLA restored A beta(25-35) induced mitochondrial dysfunction and inhibited reactive oxygen species production and amyloidogenesis. Furthermore, the Wnt/beta-catenin pathway inhibitor Dkk-1 blocked the effect of DNLA on the expression of A beta(1-4)(2) and PSD95. Conclusion: DNLA rescued A beta-mediated synaptic and mitochondrial injury and inhibited amyloidogenesis in vivo and in vitro, probably through the activation of Wnt/beta-catenin signaling pathway to protect synaptic integrity.