Studying the relationship between cell cycle and Alzheimer's disease by gold nanoparticle probes

In this study, a simple gold nanoparticle (GNP)-based colorimetric assay has been developed for studying the relationship between cell cycle and β-amyloid peptide (Aβ, the biomarker of Alzheimer's disease [AD]) expression level. It was found that Aβ expression of neuronal cells (e.g., SHG-44 cell line) is strongly dependent on cell cycle phases; that is, the Aβ expression level was highest when cells were arrested in the G1/S phase by thymidine and was lowest when they were arrested in the G2/M phase by nocodazole. This finding may improve the understanding of AD pathology and provide a new tool for anti-dementia drug development.     

Zebrafish as a tool in Alzheimer's disease research

Alzheimer's disease is the most prevalent form of neurodegenerative disease. Despite many years of intensive research our understanding of the molecular events leading to this pathology is far from complete. No effective treatments have been defined and questions surround the validity and utility of existing animal models. The zebrafish (and, in particular, its embryos) is a malleable and accessible model possessing a vertebrate neural structure and genome. Zebrafish genes orthologous to those mutated in human familial Alzheimer's disease have been defined. Work in zebrafish has permitted discovery of unique characteristics of these genes that would have been difficult to observe with other models. In this brief review we give an overview of Alzheimer's disease and transgenic animal models before examining the current contribution of zebrafish to this research area. This article is part of a Special Issue entitled Zebrafish Models of Neurological Diseases.     

Protein interaction network for Alzheimer's disease using computational approach

Alzheimer''s disease (AD) is the most common form of dementia. It is the sixth leading cause of death in old age people. Despiterecent advances in the field of drug design, the medical treatment for the disease is purely symptomatic and hardly effective. Thusthere is a need to understand the molecular mechanism behind the disease in order to improve the drug aspects of the disease. Weprovided two contributions in the field of proteomics in drug design. First, we have constructed a protein-protein interactionnetwork for Alzheimer''s disease reviewed proteins with 1412 interactions predicted among 969 proteins. Second, the diseaseproteins were given confidence scores to prioritize and then analyzed for their homology nature with respect to paralogs andhomologs. The homology persisted with the mouse giving a basis for drug design phase. The method will create a new drug designtechnique in the field of bioinformatics by linking drug design process with protein-protein interactions via signal pathways. Thismethod can be improvised for other diseases in future.     

Adult hippocampal neurogenesis in aging and Alzheimer's disease

Adult neurogenesis occurs in the subgranular zone of the hippocampal dentate gyrus and the subventricular zone of the lateral ventricles. This process is highly regulated by intrinsic and extrinsic factors, which may control the proliferation and/or maturation of neural progenitor cells. Adult-born neurons are integrated in preexisting networks and may have functional implications for adult brain. Here we attempt to summarize relevant findings concerning the physiological role of adult neurogenesis mainly focused on the subgranular zone, and to discuss the reduced neurogenesis observed during aging and the factors that have been involved in this phenomenon. Finally, we focus on hippocampal neurogenesis in Alzheimer's disease, reviewing animal models of the disease used for the study of this process and the conclusions that have been drawn in this context.     

Nucleic acid oxidation: an early feature of Alzheimer's disease

Studies of oxidative damage during the progression of Alzheimer's disease (AD) suggest its central role in disease pathogenesis. To investigate levels of nucleic acid oxidation in both early and late stages of AD, levels of multiple base adducts were quantified in nuclear and mitochondrial DNA from the superior and middle temporal gyri (SMTG), inferior parietal lobule (IPL), and cerebellum (CER) of age‐matched normal control subjects, subjects with mild cognitive impairment, preclinical AD, late‐stage AD, and non‐AD neurological disorders (diseased control; DC) using gas chromatography/mass spectrometry. Median levels of multiple DNA adducts in nuclear and mitochondrial DNA were significantly (p ≤ 0.05) elevated in the SMTG, IPL, and CER in multiple stages of AD and in DC subjects. Elevated levels of fapyguanine and fapyadenine in mitochondrial DNA suggest a hypoxic environment early in the progression of AD and in DC subjects. Overall, these data suggest that oxidative damage is an early event not only in the pathogenesis of AD but is also present in neurodegenerative diseases in general.

     

Functional effects of gut microbiota-derived metabolites in Alzheimer's disease

The precise causation of Alzheimer's disease (AD) is unknown, and the factors that contribute to its etiology are highly complicated. Numerous research has been conducted to investigate the potential impact of various factors to the risk of AD development or prevention against it. A growing body of evidence suggests to the importance of the gut microbiota-brain axis in the modulation of AD, which is characterized by altered gut microbiota composition. These changes can alter the production of microbial-derived metabolites, which may play a detrimental role in disease progression by being involved in cognitive decline, neurodegeneration, neuroinflammation, and accumulation of Aβ and tau. The focus of this review is on the relationship between the key metabolic products of the gut microbiota and AD pathogenesis in the brain. Understanding the action of microbial metabolites can open up new avenues for the development of AD treatment targets.     

Analysis of lipophilic fluorescent products in blood of Alzheimer's disease patients

Alzheimer's disease (AD) is a severe neurodegenerative disorder characterized by cognitive decline. Prodromal stage of AD, also called mild cognitive impairment (MCI), especially its amnestic type (aMCI), precedes dementia stage of AD. There are currently no reliable diagnostic biomarkers of AD in the blood. Alzheimer's disease is accompanied by increased oxidative stress in brain, which leads to oxidative damage and accumulation of free radical reaction end‐products. In our study, specific products of lipid peroxidation in the blood of AD patients were studied. Lipophilic extracts of erythrocytes (AD dementia = 19, aMCI = 27, controls = 16) and plasma (AD dementia = 11, aMCI = 17, controls = 16) were analysed by fluorescence spectroscopy. The level of these products is significantly increased in erythrocytes and plasma of AD dementia and aMCI patients versus controls. We concluded that oxidative stress end‐products are promising new biomarkers of AD, but further detailed characterisation of these products is needed.     

Data-driven modeling of mitochondrial dysfunction in Alzheimer's disease

Intracellular accumulation of oligomeric forms of β amyloid (Aβ) are now believed to play a key role in the earliest phase of Alzheimer's disease (AD) as their rise correlates well with the early symptoms of the disease. Extensive evidence points to impaired neuronal Ca²⁺ homeostasis as a direct consequence of the intracellular Aβ oligomers. However, little is known about the downstream effects of the resulting Ca²⁺ rise on the many intracellular Ca²⁺-dependent pathways. Here we use multiscale modeling in conjunction with patch-clamp electrophysiology of single inositol 1,4,5-trisphosphate (IP₃) receptor (IP₃R) and fluorescence imaging of whole-cell Ca²⁺ response, induced by exogenously applied intracellular Aβ₄₂ oligomers to show that Aβ₄₂ inflicts cytotoxicity by impairing mitochondrial function. Driven by patch-clamp experiments, we first model the kinetics of IP₃R, which is then extended to build a model for the whole-cell Ca²⁺ signals. The whole-cell model is then fitted to fluorescence signals to quantify the overall Ca²⁺ release from the endoplasmic reticulum by intracellular Aβ₄₂ oligomers through G-protein-mediated stimulation of IP₃ production. The estimated IP₃ concentration as a function of intracellular Aβ₄₂ content together with the whole-cell model allows us to show that Aβ₄₂ oligomers impair mitochondrial function through pathological Ca²⁺ uptake and the resulting reduced mitochondrial inner membrane potential, leading to an overall lower ATP and increased production of reactive oxygen species and H₂O₂. We further show that mitochondrial function can be restored by the addition of Ca²⁺ buffer EGTA, in accordance with the observed abrogation of Aβ₄₂ cytotoxicity by EGTA in our live cells experiments.     

Neuroendocrine immunity in patients with Alzheimer's disease: toward translational epigenetics

The emerging domain of epigenetics in molecular medicine finds application for a variety of patient populations. Here, we present fundamental neuroendocrine immune evidence obtained in patients with senile dementia of the Alzheimer's type (sDAT), and discuss the implications of these data from the viewpoint of translational epigenetics of Alzheimer's disease. We followed 18 subjects with mild sDAT treated with acetylcholinesterase inhibitors, and 10 control subjects matched for age in a repeated measure design every six months for 18 months. We monitored psychosocial profile (Mini-Mental State Examination, Functional Assessment Staging, Independence in Activities of Daily Living, Depression, Profile of Moods States) in parallel to immunophenotypic parameters of T cell subpopulations by flow cytometry. Based on change in the mini-mental state score at entry and at 18 months, patients with sDAT were assigned to a "fast progression" (delta greater than 2 points) or to a "slow progression" group (delta less than or equal to 2 points). The change in circulating activated T cells (CD3+Dr+) with time in patients with sDAT was significantly inversely correlated with the change in time in natural killer (NK) cytotoxic activity to cortisol modulation in these patients, which was greater in patients with fast progression, compared to slow progression sDAT. These data indicate underlying neuroendocrine immune processes during progression of sDAT. Our observations suggest that psychoimmune measures such as those we have monitored in this study provide relevant information about the evolving physiological modulation in patients with sDAT during progression of Alzheimer's disease, and point to new or improved translational epigenetic treatment interventions.     

Tau 蛋白磷酸化在阿尔茨海默病中所处的地位

阿尔茨海默病(Alzheimer’s disease,AD)是一种老年人常见的神经系统退行性疾病,是痴呆最常见的病因。AD患者越来越多,给家属及社会带来严重负担造成了巨大的家庭和社会负担,这就迫使我们进一步探讨AD发病机制。在AD的众多发病机制中,tau蛋白假说倍受青睐。在蛋白磷酸酯酶2A(protein phosphatase 2A,PP2A)、糖原合酶激酶-3β(glycogen synthase kinase-3β,GSK-3β)、细胞周期依赖性蛋白激酶-5(cyclin-dependent kinase 5,CDK-5)和Bcl-2等蛋白酶及调节蛋白作用下,微管相关蛋白tau蛋白以其异常磷酸化结构或是形成二聚体、寡聚体和神经原纤维缠结等形式,参与到AD的病理过程。Tau蛋白及其相关结构,可能启动或促进了AD的凋亡,亦可能抑制了急性凋亡却促进了慢性的神经细胞变性。揭开这一谜底,可能揭开AD病理改变的神秘面纱。     

Blood‐based biomarkers for Down syndrome and Alzheimer's disease: A systematic review

Down syndrome (DS) occurs due to triplication of chromosome 21. Individuals with DS face an elevated risk for development of Alzheimer's disease (AD) due to increased amyloid beta (Aβ) resulting from the over‐expression of the amyloid precursor protein found on chromosome 21. Diagnosis of AD among individuals with DS poses particular challenges resulting in an increased focus on alternative diagnostic methods such as blood‐based biomarkers. The aim of this review was to evaluate the current state of the literature of blood‐based biomarkers found in individuals with DS and particularly among those also diagnosed with AD or in prodromal stages (mild cognitive impairment [MCI]). A systematic review was conducted utilizing a comprehensive search strategy. Twenty‐four references were identified, of those, 22 fulfilled inclusion criteria were selected for further analysis with restriction to only plasma‐based biomarkers. Studies found Aβ to be consistently higher among individuals with DS; however, the link between Aβ peptides (Aβ1‐42 and Aβ1‐40) and AD among DS was inconsistent. Inflammatory‐based proteins were more reliably found to be elevated leading to preliminary work focused on an algorithmic approach with predominantly inflammatory‐based proteins to detect AD and MCI as well as predict risk of incidence among DS. Separate work has also shown remarkable diagnostic accuracy with the use of a single protein (NfL) as compared to combined proteomic profiles. This review serves to outline the current state of the literature and highlights the potential plasma‐based biomarkers for use in detecting AD and MCI among this at‐risk population.     

Lipids in Alzheimer's disease: A century-old story

Three neuropathological features attracted the attention of Alzheimer in his examination of the brain of Auguste Deter: abnormal fibrillary structures, cortical depositions now termed “plaques,” and glial proliferation, whereby he noted remarkable lipid granule accumulation in the glia. These features were also recorded by Perusini and Kraepelin, but by 1930 the lipoid deposits were no longer regarded by neuropathologists with great interest.     

The role of gut microbiota in pathogenesis of Alzheimer's disease

This paper describes the effects of the gut microbiota on the pathogenesis of Alzheimer's pathology by evaluating the current original key findings and identifying gaps in the knowledge required for validation. The diversity of the gut microbiota declines in the elderly and in patients with Alzheimer's disease (AD). Restoring the diversity with probiotic treatment alleviates the psychiatric and histopathological findings. This presents a problem: How does gut microbiota interact with the pathogenesis of AD? The starting point of this comprehensive review is addressing the role of bacterial metabolites and neurotransmitters in the brain under various conditions, ranging from a healthy state to ageing and disease. In the light of current literature, we describe three different linkages between the present gut microbiome hypothesis and the other major theories for the pathogenesis of AD as follows: bacterial metabolites and amyloids can trigger central nervous system inflammation and cerebrovascular degeneration; impaired gut microbiome flora inhibits the autophagy-mediated protein clearance process; and gut microbiomes can change the neurotransmitter levels in the brain through the vagal afferent fibres.     

Fractionation with ethanol of nucleic acids from viroid-infected plants

A combination of high salt and low ethanol concentration allowed the fractionation of nucleic acids extracted from viroid-infected leaves. By adding 0.4-0.5 vol of ethanol to 1 vol of a solution in 2 M LiCl of nucleic acids (containing mainly DNA, 4S, 5S, 7S, and viroid RNAs), 85% of the DNA and 75% of the 4S RNA remained in solution, from where they could be recovered by increasing the ethanol concentration, whereas almost all 5S, 7S, and viroid RNAs precipitated. When this process was repeated three times a 95% elimination of the initial DNA and 4S RNA was achieved. The method can be of special interest in viroid purification considering that DNA and 4S RNA are the most abundant contaminants in the starting solution of nucleic acids. It is suggested that the highly ordered secondary structure of viroid RNA may be responsible for its particular behavior in the ethanol fractionation of nucleic acids.     

Metabolic engineering of Corynebacterium glutamicum for production of scyllo-inositol,a drug candidate against Alzheimer's disease

Scyllo-inositol has been identified as a potential drug for the treatment of Alzheimer's disease. Therefore, cost-efficient processes for the production of this compound are desirable. In this study, we analyzed and engineered Corynebacterium glutamicum with the aim to develop competitive scyllo-inositol producer strains. Initial studies revealed that C. glutamicum naturally produces scyllo-inositol when cultured with myo-inositol as carbon source. The conversion involves NAD⁺-dependent oxidation of myo-inositol to 2-keto-myo-inositol followed by NADPH-dependent reduction to scyllo-inositol. Use of myo-inositol for biomass formation was prevented by deletion of a cluster of 16 genes involved in myo-inositol catabolism (strain MB001(DE3)Δiol1). Deletion of a second cluster of four genes (oxiC-cg3390-oxiD-oxiE) related to inositol metabolism prevented conversion of 2-keto-myo-inositol to undesired products causing brown coloration (strain MB001(DE3)Δiol1Δiol2). The two chassis strains were used for plasmid-based overproduction of myo-inositol dehydrogenase (IolG) and scyllo-inositol dehydrogenase (IolW). In BHI medium containing glucose and myo-inositol, a complete conversion of the consumed myo-inositol into scyllo-inositol was achieved with the Δiol1Δiol2 strain. To enable scyllo-inositol production from cheap carbon sources, myo-inositol 1-phosphate synthase (Ino1) and myo-inositol 1-phosphatase (ImpA), which convert glucose 6-phosphate into myo-inositol, were overproduced in addition to IolG and IolW using plasmid pSI. Strain MB001(DE3)Δiol1Δiol2 (pSI) produced 1.8 g/L scyllo-inositol from 20 g/L glucose and even 4.4 g/L scyllo-inositol from 20 g/L sucrose within 72 h. Our results demonstrate that C. glutamicum is an attractive host for the biotechnological production of scyllo-inositol and potentially further myo-inositol-derived products.