ABSTRACT
Alzheimer's Disease (AD) is a devastating neurodegenerative disorder without a cure. Here we show that mitochondrial respiratory chain complex I is an important small molecule druggable target in AD. Partial inhibition of complex I triggers the AMP-activated protein kinase-dependent signaling network leading to neuroprotection in symptomatic APP/PS1 female mice, a translational model of AD. Treatment of symptomatic APP/PS1 mice with complex I inhibitor improved energy homeostasis, synaptic activity, long-term potentiation, dendritic spine maturation, cognitive function and proteostasis, and reduced oxidative stress and inflammation in brain and periphery, ultimately blocking the ongoing neurodegeneration. Therapeutic efficacy in vivo was monitored using translational biomarkers FDG-PET, 31P NMR, and metabolomics. Cross-validation of the mouse and the human transcriptomic data from the NIH Accelerating Medicines Partnership-AD database demonstrated that pathways improved by the treatment in APP/PS1 mice, including the immune system response and neurotransmission, represent mechanisms essential for therapeutic efficacy in AD patients.
Subject(s)
Alzheimer Disease/drug therapy , Brain/drug effects , Cognition/drug effects , Electron Transport Complex I/antagonists & inhibitors , Pyrones/therapeutic use , Alzheimer Disease/metabolism , Animals , Brain/metabolism , Brain/ultrastructure , Disease Models, Animal , Drug Evaluation, Preclinical , Female , Mice, Inbred C57BL , Mice, Transgenic , Neuroprotection , Proof of Concept Study , Pyrones/pharmacology , Signal Transduction/drug effectsABSTRACT
AIM: This study aimed to explore the influence of maternal folate and vitamin B12 (B12) status during pregnancy on the incidence of low birthweight (LBW) infants. METHODS: A total of 6203 eligible women registered in seven hospitals in southern China, and 230 cases with singleton live births and 382 controls were matched for further analyses. The concentrations of serum folate and B12 were detected with chemiluminescence microparticle immunoassay on ARCHITECT i2000-1. Conditional logistic regression was used to evaluate the effects of folate and B12 levels on LBW. RESULTS: Maternal serum folate levels increased basically with increasing the period of folic acid supplementation (P trend <0.001). Moreover, maternal serum folate and B12 levels gradually decreased with the increase of gestational age (P < 0.001). Conditional logistic regressions analysis results showed increased odds ratios (OR) for LBW from the fourth to first folate quartiles (P trend <0.01) in the second trimester. Compared with the women in the highest quartile, those in the lowest quartile of serum folate in the second trimester were found with higher risk of LBW (adjusted OR = 1.67, 95% confidence interval [CI]: 1.02-2.73). However, no significant association was observed between serum folate and LBW in the first trimester or third trimester. In addition, serum B12 exhibited no significant association with LBW. CONCLUSIONS: Low serum folate levels in the second trimester significantly increases the risk of LBW amongst Chinese women with singleton pregnancies.