Brain cholesterol in normal and pathological aging

Correct lipid homeostasis at the plasma membrane is essential for cell survival and performance. These are critically challenged in the aging brain. Changes in the levels of cholesterol, a major membrane component especially enriched in neurons, accompany the brain aging process. They also occur in neurodegenerative diseases. Understanding the causes and consequences of these changes is a crucial step when trying to delay the cognitive decline, which comes with age, or to design strategies to fight neurodegenerative disorders such as Alzheimer's disease. We here review work that has contributed to this understanding.     

Ergothioneine and melatonin attenuate oxidative stress and protect against learning and memory deficits in C57BL/6J mice treated with D-galactose

Abstract

Male C57BL/6J mice treated with D-galactose (DG) were used to examine the effects of ergothioneine (EGT), melatonin (MEL), or their combination (EGT+MEL) on learning and memory abilities. The mice were divided into five groups and injected subcutaneously with DG (0.3 mL of 1% DG/mouse) except for group 1 (normal controls). Group 3 was orally supplemented with EGT [0.5 mg/kg body weight (bw)], group 4 with MEL (10 mg/kg bw, p.o.), and group 5 with EGT+MEL. EGT and MEL were provided daily for 88 days, while DG was provided between days 7 to 56. Active avoidance task and Morris water-maze task were used to evaluate learning and memory abilities. DG treatment markedly increased escape latency and decreased the number of avoidance in the active avoidance test, whereas EGT and MEL alone significantly improved the performance. DG also impaired the learning and memory abilities in the water-maze task, and EGT and MEL alone also significantly improved the performance. EGT+MEL produced the strongest effects in both tasks. EGT and MEL alone markedly decreased β-amyloid protein accumulation in the hippocampus and significantly inhibited lipid peroxidation and maintained glutathione/glutathione disulfide ratio and superoxide dismutase activity in brain tissues of DG-treated mice. MEL alone completely prevented the rise in brain acetylcholine esterase activity induced by DG, whereas EGT and EGT+MEL were only partially effective. Overall, EGT, MEL, and, in particular, the combination of EGT and MEL effectively protect against learning and memory deficits in C57BL/6J mice treated with DG, possibly through attenuation of oxidative damage.     

阿尔茨海默病患者海马中与学习记忆相关的枢纽基因鉴定及机制分析

目的：阿尔茨海默病（Alzheimer's Disease,AD）是一种以学习和记忆能力逐渐下降为显著特征的神经退行性疾病,我们通过生物信息学分析识别其相关枢纽基因,以探索潜在的靶向治疗方法。方法：本研究从Gene Expression Omnibus(GEO)数据库中提取了AD患者的基因表达数据,包括GSE5281和GSE36980,并通过GSEA数据库检索了学习与记忆相关的基因集。在GSE5281与GSE36980差异表达基因的重叠部分,我们共鉴定出158个与海马区AD相关的基因。这些基因随后被用于基因本体论（Gene Ontology, GO）和京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes, KEGG）途径富集分析,进而构建了蛋白-蛋白相互作用（Protein-Protein Interaction, PPI）网络。在识别出PPI网络中的20个枢纽基因后,我们再次进行GO和KEGG通路的富集分析,最终鉴定出3个关键的学习与记忆基因。结果：本研究发现,PPI网络中的20个枢纽基因在GO和KEGG通路的突触变化中显著富集,提示这些基因可能在突触功能的调控中发挥重要作用。此外,这些基因的富集分析结果与158个AD相关基因的分析结果呈现出相似的趋势,进一步支持其在AD病理机制中的潜在关键作用。随后,我们通过深入分析PPI网络中最为紧密连接的20个枢纽基因,结合MCODE和cytoHubba的分析结果,最终筛选并确定了3个与学习和记忆密切相关的核心枢纽基因（SNAP25、SYT4和GABRG2）。结论：SNAP25、SYT4和GABRG2可能作为AD的生物标志物和治疗靶点,为改善学习与记忆能力的逐渐下降提供了新的治疗思路。     

Design,synthesis and evaluation of novel bivalent β-carboline derivatives as multifunctional agents for the treatment of Alzheimer's disease

To develop potent multi-target ligands against Alzheimer's disease (AD), a series of novel bivalent β-carboline derivatives were designed, synthesized, and evaluated. In vitro studies revealed these compounds exhibited good multifunctional activities. In particular, compounds 8f and 8g showed the good selectivity potency on BuChE inhibition (IC₅₀?=?1.7 and 2.7?μM, respectively), Aβ_1-42 disaggregation and neuroprotection. Compared with the positive control resveratrol, 8f and 8g showed better activity in inhibiting Aβ_1-42 aggregation, with inhibitory rate 82.7% and 85.7% at 25?μM, respectively. Moreover, compounds 8e, 8f and 8g displayed excellent neuroprotective activity by ameliorating the impairment induced by H₂O₂, okadaic acid (OA) and Aβ_1-42 without cytotoxicity in SH-SY5Y cells. Thus, the present study evidently showed that compounds 8f and 8g are potent multi-functional agents against AD and might serve as promising lead candidates for further development.