Disrupted small-world brain networks in moderate Alzheimer's disease: a resting-state FMRI study

The small-world organization has been hypothesized to reflect a balance between local processing and global integration in the human brain. Previous multimodal imaging studies have consistently demonstrated that the topological architecture of the brain network is disrupted in Alzheimer's disease (AD). However, these studies have reported inconsistent results regarding the topological properties of brain alterations in AD. One potential explanation for these inconsistent results lies with the diverse homogeneity and distinct progressive stages of the AD involved in these studies, which are thought to be critical factors that might affect the results. We investigated the topological properties of brain functional networks derived from resting functional magnetic resonance imaging (fMRI) of carefully selected moderate AD patients and normal controls (NCs). Our results showed that the topological properties were found to be disrupted in AD patients, which showing increased local efficiency but decreased global efficiency. We found that the altered brain regions are mainly located in the default mode network, the temporal lobe and certain subcortical regions that are closely associated with the neuropathological changes in AD. Of note, our exploratory study revealed that the ApoE genotype modulates brain network properties, especially in AD patients.     

Interactions of oxidative stress with cellular calcium dynamics and glucose metabolism in Alzheimer's disease

Considerable evidence suggests that oxidative stress (elevated levels of reactive oxygen species), altered energy metabolism, and changes in calcium dynamics are central to Alzheimer's disease (AD). Abnormalities in each of these processes occur in AD, and they can be plausibly linked to the pathology and clinical outcome of the disease. Abnormalities in these same processes in peripheral tissues, such as fibroblasts, indicate that these are inherent properties of AD cells and are not merely a secondary response to neurodegeneration. Results in cultured cells including fibroblasts demonstrate that oxidative stress can lead to the AD-related changes in calcium and energy metabolism. Data also suggest that abnormalities in the cellular calcium stores, the ability to handle oxidative stress, and to respond to metabolic impairment link the AD-causing gene mutations to the disease process. Abnormal metabolism and oxidative stress alter the proteins and cellular processes that are modified in AD, and can be readily linked to neuronal death and brain dysfunction. Prevention and/or correction of these abnormalities are appropriate therapeutic targets.     

Leptin Dysfunction and Alzheimer’s Disease: Evidence from Cellular,Animal, and Human Studies

There is accumulating evidence from epidemiological studies that changes in body weight are associated with Alzheimer’s disease (AD) from mid-life obesity increasing the risk of developing AD to weight loss occurring at the earliest stages of AD. Therefore, factors that regulate body weight are likely to influence the development and progression of AD. The adipocyte-derived hormone leptin has emerged as a major regulator of body weight mainly by activating hypothalamic neural circuits. Leptin also has several pleotropic effects including regulating cognitive function and having neuroprotective effects, suggesting a potential link between leptin and AD. Here, we will examine the relationship between leptin and AD by reviewing the recent evidence from cellular and animal models to human studies. We present a model where leptin has a bidirectional role in AD. Not only can alterations in leptin levels and function worsen cognitive decline and progression of AD pathology, but AD pathology, in of itself, can disrupt leptin signaling, which together would lead to a downward spiral of progressive neurodegeneration and worsening body weight and systemic metabolic deficits. Collectively, these studies serve as a framework to highlight the importance of understanding the molecular mechanisms underlying the body weight and systemic metabolic deficits in AD, which has the potential to open new avenues that may ultimately lead to novel therapeutic targets and diagnostic tools.     

Pathological roles of ceramide and its metabolites in metabolic syndrome and Alzheimer's disease

The public health burden of metabolic syndrome (MetS), a multiplex risk factor that arises from insulin resistance accompanying abnormal adipose conditions, and Alzheimer's disease (AD), the most common form of dementia, continues to expand. Current available therapies for these disorders are of limited effectiveness. Recent findings have indicated that alternations in sphingolipid metabolism contribute to the development of these pathologies. Sphingolipids are major constituents of the plasma membrane, where they are known to form several types of microdomains, and are potent regulators for a variety of physiological processes. Many groups, including ours, have demonstrated that membrane sphingolipids, especially ceramide and its metabolites such as ceramide 1-phosphate, have roles in arteriosclerosis, obesity, diabetes, and inflammation associated with MetS. Aberrant sphingolipid profiles have been observed in human AD brains, and accumulated evidence has demonstrated that changes in membrane properties induced by defective sphingolipid metabolism impair generation and degradation of amyloid-β peptide (Aβ), a pathogenic agent of AD. In this review, we summarize current knowledge and pathophysiological implications of the roles of SLs in MetS and AD, to provide insight into the SL metabolic pathways as potential targets for therapy of these diseases. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology.     

Metabolic defects shared by Alzheimer's disease and diabetes: A focus on mitochondria

Type 2 diabetes (T2D) and Alzheimer's disease (AD) are two global epidemics that share several metabolic defects, such as insulin resistance, impaired glucose metabolism, and mitochondrial defects. Importantly, strong evidence demonstrates that T2D significantly increases the risk of cognitive decline and dementia, particularly AD. Here, we provide an overview of the metabolic defects that characterize and link both pathologies putting the focus on mitochondria. The biomarker potential of mitochondrial components and the therapeutic potential of some drugs that target and modulate mitochondria are also briefly discussed.     

Acceleration of phosphatidylcholine synthesis and breakdown by inhibitors of mitochondrial function in neuronal cells: a model of the membrane defect of Alzheimer's disease.

Brain cells in Alzheimer's disease (AD) exhibit a membrane defect characterized by accelerated phospholipid turnover. The mechanism responsible for this defect remains unknown. Recent studies indicate that impairment of mitochondrial function is frequently observed in AD and may be responsible for certain aspects of its pathophysiology. We show that when PC12 cells are exposed to inhibitors of mitochondrial bioenergetics, the turnover of their major membrane phospholipid, phosphatidylcholine, is accelerated, producing a pattern of metabolic changes that mimics that observed in brains of AD patients. Abnormalities of mitochondrial function may therefore underlie the membrane defect in AD.     

Prioritizing Candidate Disease Metabolites Based on Global Functional Relationships between Metabolites in the Context of Metabolic Pathways

Identification of key metabolites for complex diseases is a challenging task in today''s medicine and biology. A special disease is usually caused by the alteration of a series of functional related metabolites having a global influence on the metabolic network. Moreover, the metabolites in the same metabolic pathway are often associated with the same or similar disease. Based on these functional relationships between metabolites in the context of metabolic pathways, we here presented a pathway-based random walk method called PROFANCY for prioritization of candidate disease metabolites. Our strategy not only takes advantage of the global functional relationships between metabolites but also sufficiently exploits the functionally modular nature of metabolic networks. Our approach proved successful in prioritizing known metabolites for 71 diseases with an AUC value of 0.895. We also assessed the performance of PROFANCY on 16 disease classes and found that 4 classes achieved an AUC value over 0.95. To investigate the robustness of the PROFANCY, we repeated all the analyses in two metabolic networks and obtained similar results. Then we applied our approach to Alzheimer''s disease (AD) and found that a top ranked candidate was potentially related to AD but had not been reported previously. Furthermore, our method was applicable to prioritize the metabolites from metabolomic profiles of prostate cancer. The PROFANCY could identify prostate cancer related-metabolites that are supported by literatures but not considered to be significantly differential by traditional differential analysis. We also developed a freely accessible web-based and R-based tool at http://bioinfo.hrbmu.edu.cn/PROFANCY.     

Impact of fire on active layer and permafrost microbial communities and metagenomes in an upland Alaskan boreal forest

Permafrost soils are large reservoirs of potentially labile carbon (C). Understanding the dynamics of C release from these soils requires us to account for the impact of wildfires, which are increasing in frequency as the climate changes. Boreal wildfires contribute to global emission of greenhouse gases (GHG—CO₂, CH₄ and N₂O) and indirectly result in the thawing of near-surface permafrost. In this study, we aimed to define the impact of fire on soil microbial communities and metabolic potential for GHG fluxes in samples collected up to 1 m depth from an upland black spruce forest near Nome Creek, Alaska. We measured geochemistry, GHG fluxes, potential soil enzyme activities and microbial community structure via 16SrRNA gene and metagenome sequencing. We found that soil moisture, C content and the potential for respiration were reduced by fire, as were microbial community diversity and metabolic potential. There were shifts in dominance of several microbial community members, including a higher abundance of candidate phylum AD3 after fire. The metagenome data showed that fire had a pervasive impact on genes involved in carbohydrate metabolism, methanogenesis and the nitrogen cycle. Although fire resulted in an immediate release of CO₂ from surface soils, our results suggest that the potential for emission of GHG was ultimately reduced at all soil depths over the longer term. Because of the size of the permafrost C reservoir, these results are crucial for understanding whether fire produces a positive or negative feedback loop contributing to the global C cycle.     

Cortical gyrification and sulcal spans in early stage Alzheimer's disease

Alzheimer's disease (AD) is characterized by an insidious onset of progressive cerebral atrophy and cognitive decline. Previous research suggests that cortical folding and sulcal width are associated with cognitive function in elderly individuals, and the aim of the present study was to investigate these morphological measures in patients with AD. The sample contained 161 participants, comprising 80 normal controls, 57 patients with very mild AD, and 24 patients with mild AD. From 3D T1-weighted brain scans, automated methods were used to calculate an index of global cortex gyrification and the width of five individual sulci: superior frontal, intra-parietal, superior temporal, central, and Sylvian fissure. We found that global cortex gyrification decreased with increasing severity of AD, and that the width of all individual sulci investigated other than the intra-parietal sulcus was greater in patients with mild AD than in controls. We also found that cognitive functioning, as assessed by Mini-Mental State Examination (MMSE) scores, decreased as global cortex gyrification decreased. MMSE scores also decreased in association with a widening of all individual sulci investigated other than the intra-parietal sulcus. The results suggest that abnormalities of global cortex gyrification and regional sulcal span are characteristic of patients with even very mild AD, and could thus facilitate the early diagnosis of this condition.     

Blood markers of oxidative stress in Alzheimer's disease

Alzheimer's disease (AD) represents a highly common form of dementia, but can be diagnosed in the earlier stages before dementia onset. Early diagnosis is crucial for successful therapeutic intervention. The introduction of new diagnostic biomarkers for AD is aimed at detecting underlying brain pathology. These biomarkers reflect structural or biochemical changes related to AD. Examination of cerebrospinal fluid has many drawbacks; therefore, the search for sensitive and specific blood markers is ongoing. Investigation is mainly focused on upstream processes, among which oxidative stress in the brain is of particular interest. Products of oxidative stress may diffuse into the blood and evaluating them can contribute to diagnosis of AD. However, results of blood oxidative stress markers are not consistent among various studies, as documented in this review. To find a specific biochemical marker for AD, we should concentrate on specific metabolic products formed in the brain. Specific fluorescent intermediates of brain lipid peroxidation may represent such candidates as the composition of brain phospholipids is unique. They are small lipophilic molecules and can diffuse into the blood stream, where they can then be detected. We propose that these fluorescent products are potential candidates for blood biomarkers of AD.     

Diminished O-GlcNAcylation in Alzheimer's disease is strongly correlated with mitochondrial anomalies

Uncover the initial cause(s) underlying Alzheimer's disease (AD) pathology is imperative for the development of new therapeutic interventions to counteract AD-related symptomatology and neuropathology in a timely manner. The early stages of AD are characterized by a brain hypometabolic state as denoted by faulty glucose uptake and utilization and abnormal mitochondrial function and distribution which, ultimately, culminates in synaptic “starvation” and neuronal degeneration. Importantly, it was recently recognized that the post-translational modification β-N-acetylglucosamine (O-GlcNAc) modulates mitochondrial function, motility and distribution being proposed to act as a nutrient sensor that links glucose and the metabolic status to neuronal function. Using post-mortem human brain tissue, brain samples from the triple transgenic mouse model of AD (3xTg-AD) and in vitro models of AD (differentiated SH-SY5Y cells exposed to AD-mimicking conditions), the present study is aimed to clarify whether O-GlcNAcylation, the posttranslational modification of intracellular proteins by O-GlcNAc, contributes to “mitochondrial pathology” in AD and its potential as a therapeutic target. A reduction in global O-GlcNAcylation levels was observed in the brain cortex and hippocampus of AD subjects. Moreover, GlcNAcylation levels are higher in mature mice but the levels of this posttranslational modification are lower in 3xTg-AD mice when compared to control mice. The in vitro models of AD also exhibited a marked reduction in global O-GlcNAcylation levels, which was strongly correlated with hampered mitochondrial bioenergetic function, disruption of the mitochondrial network and loss of cell viability. Conversely, the pharmacological modulation of O-GlcNAcylation levels with Thiamet-G restored O-GlcNAcylation levels and cell viability in the in vitro models of AD. Overall, these results suggest that O-GlcNAcylation is involved in AD pathology functioning as a potential link between mitochondrial energetic crisis and synaptic and neuronal degeneration. This posttranslational modification represents a promising therapeutic target to tackle this devastating neurodegenerative disease.     

Processing of neuropeptide Y, galanin, and somatostatin in the cerebrospinal fluid of patients with Alzheimer’s disease and frontotemporal dementia

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are two prevalent neurodegenerative disorders for which the causes are unknown, except in rare familial cases. Several changes in neuropeptide levels as measured by radioimmunoassay (RIA) have been observed in these illnesses. Somatostatin (SOM) levels in cerebrospinal fluid (CSF) are consistently decreased in AD and FTD. Neuropeptide Y (NPY) levels are decreased in AD, but normal in FTD. Galanin (GAL) levels increase with the duration of illness in AD patients. The majority of studies of neuropeptides in CSF have not been verified by HPLC. The observed decrease in a neuropeptide level as measured by RIA may therefore reflect an altered synthesis or extracellular processing, resulting in neuropeptide fragments that may or may not be detected by RIA. Matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-MS) has been shown to be a powerful technique in the analysis of biological materials without any pre-treatment, by detecting peptides and proteins at a specific mass-to-charge (m/z) ratio. We studied the processing of the neuropeptides NPY, NPY, SOM and GAL in the cerebrospinal fluid of patients with AD (n = 3), FTD (n = 3) and controls (n = 2) using MALDI-MS. We found that considerable inter-individual variability exists in the rate of neuropeptide metabolism in CSF, as well as the number of peptide fragments formed. Certain patients showed differences in the processing of specific neuropeptides, relative to other patients and controls. This analysis of the metabolic processing of neuropeptides in CSF yielded a large amount of data for each individual studied. Further studies are required to determine the changes in neuropeptide processing that can be associated with AD and FTD. With further investigations using MALDI-MS analysis, it may be possible to identify a neuropeptide fragment or processing enzyme that can be correlated to these disease states.     

Global spread of hypoxia in freshwater ecosystems during the last three centuries is caused by rising local human pressure

The spread of hypoxia is a threat to aquatic ecosystem functions and services as well as to biodiversity. However, sparse long‐term monitoring of lake ecosystems has prevented reconstruction of global hypoxia dynamics while inhibiting investigations into its causes and assessing the resilience capacity of these systems. This study compiles the onset and duration of hypoxia recorded in sediments of 365 lakes worldwide since AD 1700, showing that lacustrine hypoxia started spreading before AD 1900, 70 years prior to hypoxia in coastal zones. This study also shows that the increase of human activities and nutrient release is leading to hypoxia onset. No correlations were found with changes in precipitation or temperature. There is no evidence for a post‐1980s return to well‐oxygenated lacustrine conditions in industrialized countries despite the implementation of restoration programs. The apparent establishment of stable hypoxic conditions prior to AD 1900 highlights the challenges of a growing nutrient demand, accompanied by increasing global nutrient emissions of our industrialized societies, and climate change.     

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.     

Metabolic profiling of human CD4+ cells following treatment with methotrexate and anti-TNF-α infliximab

The autoimmune process in rheumatoid arthritis depends on activation of immune cells, which utilize intracellular kinases to respond to external stimuli such as cytokines, immune complexes, and antigens. CD4+ T cells comprise a large proportion of the inflammatory cells that invade the synovial tissue and may therefore be a cell type of pathogenic importance. Both methotrexate and infliximab are effective in the treatment of inflammatory arthritis; however, the biological effects triggered by these treatments and the biochemical mechanisms underlining the cell response are still not fully understood. Thus, in this study the global metabolic changes associated with methotrexate or infliximab treatment of isolated human CD4+ T cells were examined using gas chromatography/mass spectrometry or liquid chromatography/mass spectrometry. In total 148 metabolites involved in selective pathways were found to be significantly altered. Overall, the changes observed are likely to reflect the effort of CD4+ cells to increase the production of cellular reducing power to offset the cellular stress exerted by treatment. Importantly, analysis of the global metabolic changes associated with MTX or infliximab treatment of isolated human CD4+ T cells suggested that the toxicity associated with these agents is minimal when used at clinically relevant concentrations.     

Loss of 'small-world' networks in Alzheimer's disease: graph analysis of FMRI resting-state functional connectivity

Background

Local network connectivity disruptions in Alzheimer''s disease patients have been found using graph analysis in BOLD fMRI. Other studies using MEG and cortical thickness measures, however, show more global long distance connectivity changes, both in functional and structural imaging data. The form and role of functional connectivity changes thus remains ambiguous. The current study shows more conclusive data on connectivity changes in early AD using graph analysis on resting-state condition fMRI data.

Methodology/Principal Findings

18 mild AD patients and 21 healthy age-matched control subjects without memory complaints were investigated in resting-state condition with MRI at 1.5 Tesla. Functional coupling between brain regions was calculated on the basis of pair-wise synchronizations between regional time-series. Local (cluster coefficient) and global (path length) network measures were quantitatively defined. Compared to controls, the characteristic path length of AD functional networks is closer to the theoretical values of random networks, while no significant differences were found in cluster coefficient. The whole-brain average synchronization does not differ between Alzheimer and healthy control groups. Post-hoc analysis of the regional synchronization reveals increased AD synchronization involving the frontal cortices and generalized decreases located at the parietal and occipital regions. This effectively translates in a global reduction of functional long-distance links between frontal and caudal brain regions.

Conclusions/Significance

We present evidence of AD-induced changes in global brain functional connectivity specifically affecting long-distance connectivity. This finding is highly relevant for it supports the anterior-posterior disconnection theory and its role in AD. Our results can be interpreted as reflecting the randomization of the brain functional networks in AD, further suggesting a loss of global information integration in disease.