3-(2-4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3h)-quinazolinone and Alzheimer-Disease

Corallodiscus flabellata B. L. Burtt (CF) is a Chinese folk herb with reported potential for the treatment of Alzheimer's disease (AD). 3,4-Dihydroxyphenylethanol-8-O-[4-O-trans-caffeoyl-β-D-apiofuranosyl-(1→3)-β-D-glucopyranosyl (1→6)][1]-β-D-glucopyranoside (SDC-1-8) and hydroxytyrosol (HT) are two polyphenolic compounds isolated from CF. The aim of this study was to investigate the protective effects of SDC-1-8 and HT on an Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Mice; Molecular Docking Simulation; Peptide Fragments; Polyphenols; Rats

Mitochondrial dysfunction is considered an early event of Alzheimer disease (AD). D-ribose is a natural monosaccharide that exists in cells, especially in mitochondria, and can lead to cognitive dysfunction. However, the reason for this is unclear. Berberine (BBR) is an isoquinoline alkaloid that can target mitochondria and has great prospect in the treatment of AD. The methylation of PINK1 reinforces the burden of Alzheimer's pathology. This study explores the role of BBR and D-ribose in the mitophagy and cognitive function of AD related to DNA methylation.

Topics: Alzheimer Disease; Animals; Berberine; Mice; Mitophagy; Protein Kinases; Ribose; Ubiquitin-Protein Ligases

The purpose of our study was to determine the synergistic protective effects of mitochondria-targeted antioxidant SS31 and mitochondria division inhibitor 1 (Mdivi1) in Alzheimer's disease (AD). Using biochemical methods, we assessed mitochondrial function by measuring the levels of hydrogen peroxide, lipid peroxidation, cytochrome c oxidase activity, mitochondrial ATP, and GTPase Drp1 enzymatic activity in mutant AβPP cells. Using biochemical methods, we also measured cell survival and apoptotic cell death. Amyloid-β (Aβ) levels were measured using sandwich ELISA, and using real-time quantitative RT-PCR, we assessed mtDNA (mtDNA) copy number in relation to nuclear DNA (nDNA) in all groups of cells. We found significantly reduced levels of Aβ40 and Aβ42 in mutant AβPP cells treated with SS31, Mdivi1, and SS31+Mdivi1, and the reduction of Aβ42 levels were much higher in SS31+Mdivi1 treated cells than individual treatments of SS31 and Mdivi1. The levels of mtDNA copy number and cell survival were significantly increased in SS31, Mdivi1, and SS31+Mdivi1 treated mutant AβPP cells; however, the increased levels of mtDNA copy number and cell survival were much higher in SS31+Mdivi1 treated cells than individual treatments of SS31 and Mdivi1. Mitochondrial dysfunction is significantly reduced in SS31, Mdivi1, and SS31+Mdivi1 treated mutant AβPP cells; however, the reduction is much higher in cells treated with both SS31+Mdvi1. Similarly, GTPase Drp1 activity is reduced in all treatments, but reduced much higher in SS31+Mdivi1 treated cells. These observations strongly suggest that combined treatment of SS31+Mdivi1 is effective than individual treatments of SS31 and Mdivi1. Therefore, we propose that combined treatment of SS31+Mdivi1 is a better therapeutic strategy for AD. Ours is the first study to investigate combined treatment of mitochondria-targeted antioxidant SS31 and mitochondrial division inhibitor 1 in AD neurons.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Apoptosis; Cell Line, Tumor; Cell Survival; DNA, Mitochondrial; Mice; Mitochondria; Mutation; Neuroprotective Agents; Oligopeptides; Peptide Fragments; Quinazolinones

Mitochondrial dysfunction is an early prominent feature in susceptible neurons in the brain of patients with Alzheimer's disease, which likely plays a critical role in the pathogenesis of disease. Increasing evidence suggests abnormal mitochondrial dynamics as important underlying mechanisms. In this study, we characterized marked mitochondrial fragmentation and abnormal mitochondrial distribution in the pyramidal neurons along with mitochondrial dysfunction in the brain of Alzheimer's disease mouse model CRND8 as early as 3 months of age before the accumulation of amyloid pathology. To establish the pathogenic significance of these abnormalities, we inhibited mitochondrial fragmentation by the treatment of mitochondrial division inhibitor 1 (mdivi-1), a mitochondrial fission inhibitor. Mdivi-1 treatment could rescue both mitochondrial fragmentation and distribution deficits and improve mitochondrial function in the CRND8 neurons both in vitro and in vivo. More importantly, the amelioration of mitochondrial dynamic deficits by mdivi-1 treatment markedly decreased extracellular amyloid deposition and Aβ1-42/Aβ1-40 ratio, prevented the development of cognitive deficits in Y-maze test and improved synaptic parameters. Our findings support the notion that abnormal mitochondrial dynamics plays an early and causal role in mitochondrial dysfunction and Alzheimer's disease-related pathological and cognitive impairments in vivo and indicate the potential value of restoration of mitochondrial dynamics as an innovative therapeutic strategy for Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloidogenic Proteins; Animals; Brain; Cognition Disorders; Disease Models, Animal; Mice; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins; Neurons; Pyramidal Cells; Quinazolinones

Mitochondrial dysfunction is an early pathological feature of Alzheimer's disease (AD). The underlying mechanisms and strategies to repair it remain unclear. Here, we demonstrate for the first time the direct consequences and potential mechanisms of mitochondrial functional defects associated with abnormal mitochondrial dynamics in AD. Using cytoplasmic hybrid (cybrid) neurons with incorporated platelet mitochondria from AD and age-matched non-AD human subjects into mitochondrial DNA (mtDNA)-depleted neuronal cells, we observed that AD cybrid cells had significant changes in morphology and function; such changes associate with altered expression and distribution of dynamin-like protein (DLP1) and mitofusin 2 (Mfn2). Treatment with antioxidant protects against AD mitochondria-induced extracellular signal-regulated kinase (ERK) activation and mitochondrial fission-fusion imbalances. Notably, inhibition of ERK activation not only attenuates aberrant mitochondrial morphology and function but also restores the mitochondrial fission and fusion balance. These effects suggest a role of oxidative stress-mediated ERK signal transduction in modulation of mitochondrial fission and fusion events. Further, blockade of the mitochondrial fission protein DLP1 by a genetic manipulation with a dominant negative DLP1 (DLP1(K38A)), its expression with siRNA-DLP1, or inhibition of mitochondrial division with mdivi-1 attenuates mitochondrial functional defects observed in AD cybrid cells. Our results provide new insights into mitochondrial dysfunction resulting from changes in the ERK-fission/fusion (DLP1) machinery and signaling pathway. The protective effect of mdivi-1 and inhibition of ERK signaling on maintenance of normal mitochondrial structure and function holds promise as a potential novel therapeutic strategy for AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Antioxidants; Dynamins; Extracellular Signal-Regulated MAP Kinases; Female; GTP Phosphohydrolases; Humans; Hybrid Cells; Immunoblotting; Male; Microtubule-Associated Proteins; Middle Aged; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Models, Biological; Mutation; Neurons; Probucol; Quinazolinones; Reactive Oxygen Species; RNA Interference; Signal Transduction