Discovery Of New Drugs Targeting The Oxidative Stress And Implication For The Treatment Of Alzheimer's Disease

Alzheimer's disease (AD), which accounts for60%of the dementia, is the most prevalent neurodegenerative disease, with typical pathological abnormalities including amyloid plaques, neurofibrillary tangles and neuron death. The oxidative stress and mitochondrial dysfunction induced by beta-Amyloid (A(3) is demonstrated to play a critical role in AD pathogenesis.Objective:To investigate the effects of Hopeahainol A (HopA) and Diammonium glycyrrhizinate (DG) on the Aβ1-42-induced neurotocity.Methods:(1) HPLC, electron microscopy analysis and immunostaining were used to determine the role of HopA on the aggreration of Aβ1-42in vitro and in vivo The oxidative stress in the cortex and hippocampus of APP/PS1mice were quantificated by the ELISA kit. Long term potentiation (LTP) was measured using a high-frequency stimulus (HFS) protocol. The cognitive and learning ability was assessed by the Morris water maze test.(2) The viability of neurons was measured by MTT, LDH assay and AnnexinV/PI staining. The expression of peroxisome proliferator-activated receptor gamma coactivator1α (PGC-la) was determined by Real-time PCR and Western blot. A series of truncated promoter plasmids of PGC-1a were constructed to explore the potential binding sites for DG. The cognitive and learning ability was assessed by the Morris water maze test.Results:(1) HopA was able to cross the blood-brain barrier (BBB) quickly, inhibit the oxidative stress and improve the learning and memory in APP/PS1mice. HopA could rescue the LTP induction by protecting synaptic function from Aβ1-42-induced damage. Furthermore, HopA decreased the accumulation of AP in vivo and in vitro.(2) Diammonium glycyrrhizinate (DG) could protect against Aβ-induced neuron apoptosis and improve the learning and memory in Aβ-induced AD mice. In addition, DG inhibited the oxidative stress and mitochondrial dysfunction in vivo and in vitro partially through activating peroxisome proliferator-activated receptor gamma coactivator1α (PGC-1a). Furthermore, DG induced the transcriptional activity of PGC-la, and the results of truncated promoter analysis indicated that cyclic AMP response element binding (CREB) contributed to the activation of PGC-la.Conclusion:Oxidative stress played an important role in the pathogenesis of AD. HopA and DG could inhibit the neurotoxity of Aβ by modulating ABAD and PGC-1α, reapectively, suggesting that theses two agents were potential drugs for AD treatment.