TY - JOUR
T1 - Beneficial synergistic effects of microdose lithium with pyrroloquinoline quinone in an Alzheimer's disease mouse model
AU - Zhao, Lei
AU - Gong, Neng
AU - Liu, Meng
AU - Pan, Xiaoli
AU - Sang, Shaoming
AU - Sun, Xiaojing
AU - Yu, Zhe
AU - Fang, Qi
AU - Zhao, Na
AU - Fei, Guoqiang
AU - Jin, Lirong
AU - Zhong, Chunjiu
AU - Xu, Tianle
N1 - Funding Information:
The authors thank Dr Xiang Yu for critical reading and discussions of the manuscript. This study is supported by 973 project (grant no 2011CBA00400), the National Natural Science Foundation of China (grant no 81071019 ), key fund for developing new drugs from State Scientific & Technological Ministry of China (grant no 2011ZX09102-003 ), fund for outstanding academic leaders in Shanghai (11XD1401500), and fund for International cooperation in Shanghai (10430709600).
Publisher Copyright:
© 2014 Elsevier Inc.
PY - 2014/12/1
Y1 - 2014/12/1
N2 - 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 12mg/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 100mg/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.
AB - 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 12mg/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 100mg/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.
KW - Alzheimer's disease
KW - Glycogen synthase kinase-3
KW - Lithium
KW - Pyrroloquinoline quinone
KW - β-Amyloid-binding alcohol dehydrogenase
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U2 - 10.1016/j.neurobiolaging.2014.06.003
DO - 10.1016/j.neurobiolaging.2014.06.003
M3 - Article
C2 - 25018109
AN - SCOPUS:84911439045
VL - 35
SP - 2736
EP - 2745
JO - Neurobiology of Aging
JF - Neurobiology of Aging
SN - 0197-4580
IS - 12
ER -