title: 3-Hydroxybutyrate methyl ester as a potential drug against Alzheimer's disease via mitochondria protection mechanism.
abstract: Alzheimer's disease (AD) is induced by many reasons, including decreased cellular utilization of glucose and brain cell mitochondrial damages. Degradation product of microbially synthesized polyhydroxybutyrate (PHB), namely, 3-hydroxybutyrate (3HB), can be an alternative to glucose during sustained hypoglycemia. In this study, the derivative of 3HB, 3-hydroxybutyrate methyl ester (HBME), was used by cells as an alternative to glucose. HBME inhibited cell apoptosis under glucose deprivation, rescued activities of mitochondrial respiratory chain complexes that were impaired in AD patients and decreased the generation of ROS. Meanwhile, HBME stabilized the mitochondrial membrane potential. In vivo studies showed that HBME crossed the blood brain barrier easier compared with charged 3HB, resulting in a better bioavailability. AD mice treated with HBME performed significantly better (p < 0.05) in the Morris water maze compared with other groups, demonstrating that HBME has a positive in vivo pharmaceutical effect to improve the spatial learning and working memory of mice. A reduced amyloid-β deposition in mouse brains after intragastric administration of HBME was also observed. Combined with the in vitro and in vivo results, HBME was proposed to be a drug candidate against AD, its working mechanism appeared to be mediated by various effects of protecting mitochondrial damages.
authors.affiliation: MOE Key Lab of Bioinformatics, Department of Biological Science and Biotechnology, School of Life Sciences, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Junyu
authors.initials: J
authors.lastname: Zhang
authors.forename: Qian
authors.initials: Q
authors.lastname: Cao
authors.forename: Shaowu
authors.initials: S
authors.lastname: Li
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Lu
authors.forename: Yongxi
authors.initials: Y
authors.lastname: Zhao
authors.forename: Ji-Song
authors.initials: JS
authors.lastname: Guan
authors.forename: Jin-Chun
authors.initials: JC
authors.lastname: Chen
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wu
authors.forename: Guo-Qiang
authors.initials: GQ
authors.lastname: Chen
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001284:Atrophy; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004579:Electron Transport / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D006885:Hydroxybutyrates / Q000493:pharmacokinetics / Q000494:pharmacology; D007858:Learning / Q000187:drug effects; D008279:Magnetic Resonance Imaging; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008570:Memory, Short-Term / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D016716:PC12 Cells; D000091402:Prohibitins; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C539306:3-hydroxybutyrate methyl ester; D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D006885:Hydroxybutyrates; D018696:Neuroprotective Agents; C000717332:Phb protein, rat; D000091402:Prohibitins; D053148:Caspase 3; D005947:Glucose; D020155:3-Hydroxybutyric Acid
keywords: 3-Hydroxybutyrate methyl ester; Alzheimer's disease; Mitochondria; PHB