title: Beneficial synergistic effects of microdose lithium with pyrroloquinoline quinone in an Alzheimer's disease mouse model.
abstract: Alzheimer's disease (AD) is a complicated, neurodegenerative disorder involving multifactorial pathogeneses and still lacks effective clinical treatment. Recent studies show that lithium exerts disease-modifying effects against AD. However, the intolerant side effects at conventional effective dosage limit the clinical use of lithium in treating AD. To explore a novel AD treatment strategy with microdose lithium, we designed and synthesized a new chemical, tri-lithium pyrroloquinoline quinone (Li3PQQ), to study the synergistic effects of low-dose lithium and pyrroloquinoline quinone, a native compound with powerful antioxidation and mitochondrial amelioration. The results showed that Li3PQQ at a relative low dose (6 and 12 mg/kg) exhibited more powerful effects in restoring the impairment of learning and memory, facilitating hippocampal long-term potentiation, and reducing cerebral amyloid deposition and phosphorylated tau level in APP/PS1 transgenic mice than that of lithium chloride at both low and high dose (5 and 100 mg/kg). We further found that Li3PQQ inhibited the activity of glycogen synthase kinase-3 and increased the activity of β-amyloid-binding alcohol dehydrogenase, which might underlie the beneficial effects of Li3PQQ on APP/PS1 transgenic mice. Our study demonstrated the efficacy of a novel AD therapeutic strategy targeting at multiple disease-causing mechanisms through the synergistic effects of microdose lithium and pyrroloquinoline quinone.
authors.affiliation: Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Neng
authors.initials: N
authors.lastname: Gong
authors.affiliation: Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Pan
authors.affiliation: State Key Laboratory of Medical Neurobiology, Institute of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Shaoming
authors.initials: S
authors.lastname: Sang
authors.affiliation: Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Sun
authors.affiliation: Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Fang
authors.affiliation: Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Na
authors.initials: N
authors.lastname: Zhao
authors.affiliation: Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Fei
authors.affiliation: Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Lirong
authors.initials: L
authors.lastname: Jin
authors.affiliation: Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China; State Key Laboratory of Medical Neurobiology, Institute of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address: zhongcj@163.com.
authors.forename: Chunjiu
authors.initials: C
authors.lastname: Zhong
authors.affiliation: Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Tianle
authors.initials: T
authors.lastname: Xu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000975:Antioxidants / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D007858:Learning / Q000187:drug effects; D018020:Lithium Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D017774:Long-Term Potentiation / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008822:Mice, Transgenic; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000928:Antidepressive Agents; D000975:Antioxidants; D018020:Lithium Compounds; D011758:Pyrroles; D011804:Quinolines; C410406:pyrroloquinoline; D016875:tau Proteins; D038362:Glycogen Synthase Kinase 3
keywords: Alzheimer's disease; Glycogen synthase kinase-3; Lithium; Pyrroloquinoline quinone; β-Amyloid-binding alcohol dehydrogenase