3-8-dihydroxy-6h-dibenzo(b-d)pyran-6-one and epigallocatechin-gallate

In the current study, for the first time, we study mitophagy enhancer urolithin A and a combination of urolithin A+green tea extract EGCG against human Aβ peptide-induced mitochondrial and synaptic, dendritic, inflammatory toxicities and behavioral changes in humanized homozygous amyloid beta knockin (hAbKI) mice of late-onset Alzheimer's disease (AD). Our findings reveal significantly increased positive effects of urolithin A and a combination treatment of urolithin A+EGCG in hAbKI mice for phenotypic behavioral changes including motor coordination, locomotion/exploratory activity, spatial learning and working memory. mRNA and protein levels of mitochondrial fusion, synaptic, mitophagy and autophagy genes were upregulated, and mitochondrial fission genes are downregulated in urolithin A and combine treatment in hAbKI mice; however, the effect is stronger in combined treatment. Immunofluorescence analysis of hippocampal brain sections shows similar findings of mRNA and protein levels. Mitochondrial dysfunction is significantly reduced in both treatment groups, but a stronger reduction is observed in combined treatment. Dendritic spines and lengths are significantly increased in both treatment groups, but the effect is stronger in combined treatment. The fragmented number of mitochondria is reduced, and mitochondrial length is increased, and mitophagosomal formations are increased in both the groups, but the effect is stronger in the combined treatment. The levels of amyloid beta (Aβ) 40 and Aβ42 are reduced in both treatments, however, the reduction is higher for combined treatment. These observations suggest that urolithin A is protective against human Aβ peptide-induced toxicities; however, combined treatment of urolithin A+EGCG is effective and stronger, indicating that combined therapy is promising to treat late-onset AD patients.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Catechin; Coumarins; Humans; Mice; Mitochondrial Dynamics; RNA, Messenger

The purpose of our study is to determine the protective effects of mitophagy enhancers against phosphorylated tau (P-tau)-induced mitochondrial and synaptic toxicities in Alzheimer's disease (AD). Mitochondrial abnormalities, including defective mitochondrial dynamics, biogenesis, axonal transport and impaired clearance of dead mitochondria are linked to P-tau in AD. Mitophagy enhancers are potential therapeutic candidates to clear dead mitochondria and improve synaptic and cognitive functions in AD. We recently optimized the doses of mitophagy enhancers urolithin A, actinonin, tomatidine, nicotinamide riboside in immortalized mouse primary hippocampal (HT22) neurons. In the current study, we treated mutant Tau expressed in HT22 (mTau-HT22) cells with mitophagy enhancers and assessed mRNA and protein levels of mitochondrial/synaptic genes, cell survival and mitochondrial respiration. We also assessed mitochondrial morphology in mTau-HT22 cells treated and untreated with mitophagy enhancers. Mutant Tau-HT22 cells showed increased fission, decreased fusion, synaptic & mitophagy genes, reduced cell survival and defective mitochondrial respiration. However, these events were reversed in mitophagy enhancers treated mTau-HT22 cells. Cell survival was increased, mRNA and protein levels of mitochondrial fusion, synaptic and mitophagy genes were increased, and mitochondrial fragmentation is reduced in mitophagy enhancers treated mTau-HT22 cells. Further, urolithin A showed strongest protective effects among all enhancers tested in AD. Our combination treatments of urolithin A + EGCG, addition to urolithin A and EGCG individual treatment revealed that combination treatments approach is even stronger than urolithin A treatment. Based on these findings, we cautiously propose that mitophagy enhancers are promising therapeutic drugs to treat mitophagy in patients with AD.

Topics: Alzheimer Disease; Animals; Catechin; Cell Line; Coumarins; DNA-Binding Proteins; High Mobility Group Proteins; Hippocampus; Mice; Mitochondria; Mitochondrial Dynamics; Mitophagy; Neurons; NF-E2-Related Factor 2; Nuclear Respiratory Factor 1; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphorylation; Synapses; Synaptophysin; tau Proteins