Discovery of 4′-OH-flurbiprofen Mannich base derivatives as potential Alzheimer’s disease treatment with multiple inhibitory activities

A series of 4′-OH flurbiprofen Mannich base derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer’s disease. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound 8n demonstrated the best inhibitory effects on self-induced Aβ_1-42 aggregation (65.03% at 25.0?μM). Moreover, this representative compound also exhibited good antioxidant activity, biometal chelating ability and anti-neuroinflammatory activity in vitro. Furthermore, compound 8n displayed appropriate blood-brain barrier permeability. These multifunctional properties highlight compound 8n as promising candidate for further development of multi-functional drugs against AD.     

Anti-cholinesterase hybrids as multi-target-directed ligands against Alzheimer’s disease (1998–2018)

Alzheimer’s disease (AD) is a genetically complex, progressive and irreversible neurodegenerative disorder of the brain which involves multiple associated etiological targets. The complex pathogenesis of AD gave rise to multi-target-directed ligands (MTDLs) principle to combat this dreaded disease. Within this approach, the design and synthesis of hybrids prevailed greatly because of their capability to simultaneously target the intertwined pathogenesis components of the disease. The hybrids include pharmacophoric hybridization of two or more established chemical scaffolds endowed with the desired pharmacological properties into a single moiety. In AD, the primary foundation of medication therapy and drug design strategies includes the inhibition of cholinesterase (ChE) enzymes. Hence the development of ChE inhibition based hybrids is the central choice of AD medicinal chemistry research. To illustrate the progress of ChE inhibition based hybrids and novel targets, we reviewed the medicinal chemistry and pharmacological properties of the multi-target molecules published since 1998-December 2018. We hope that this article will allow the readers to easily follow the evolution of this prominent medicinal chemistry approach to develop a more efficient inhibitor.     

Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment

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无菌APPswe/PS1ΔE9双转基因小鼠模型建立及脑内斑块变化初步观察

目的 使用剖宫产净化方法建立无菌APPswe/PS1ΔE9(PAP)双转基因小鼠模型并对动物脑内斑块沉积情况进行初步观察,为研究肠道菌群与阿尔茨海默症关系提供新的动物模型。方法 选择阳性PAP雄性杂合子鼠与经产的C57野生型雌鼠1∶2进行交配。怀孕母鼠在超净工作台内行剖宫产手术,用无菌ICR小鼠代乳。术后每个月进行无菌状态检测;PCR方法检测剖宫产所得PAP仔鼠的基因型;免疫组化方法定量检测9月龄PAP小鼠脑内斑块变化情况。结果 实施剖宫产手术12例,获仔鼠66只,剖宫产存活率及离乳存活率分别为95.45%(63/66)和95.24%(60/63),净化后按国标检测无菌状态均为合格。免疫组化结果显示9月龄无菌PAP小鼠海马内斑块较同月龄SPF级动物减少。结论 通过剖宫产净化技术去除了PAP小鼠携带的菌群,9月龄无菌PAP小鼠脑内斑块减少。     

Single-Cell Sequencing of iPSC-Dopamine Neurons Reconstructs Disease Progression and Identifies HDAC4 as a Regulator of Parkinson Cell Phenotypes

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Human Hippocampal Neurogenesis Persists in Aged Adults and Alzheimer’s Disease Patients

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Cell-Type-Specific Gene Expression Profiling in Adult Mouse Brain Reveals Normal and Disease-State Signatures

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Fasting-Mimicking Diet Modulates Microbiota and Promotes Intestinal Regeneration to Reduce Inflammatory Bowel Disease Pathology

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