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Vascular dementia (VaD) is one of the most common causes of dementia amongst the elderly. Despite this, the molecular basis of VaD remains poorly characterised when compared to other age-related dementias. Probably as a result, therapeutic options are largely restricted to repurposing medication currently used in Alzheimer’s disease (AD) which, however, offer limited therapeutic benefit. Pervasive cerebral elevations of urea have recently been reported in AD, Huntington’s disease (HD), and Parkinson’s disease dementia (PDD); however, a similar analysis was not yet available for VaD. Here we utilised ultra-high-performance liquid chromatography tandem-mass spectrometry (UHPLC-MS/MS) to measure urea levels from seven cerebral regions in post-mortem tissue from cases of VaD (n = 10) and matched controls (n = 8/9). Brain-urea measurements from our previous investigations of AD, HD, and PDD, quantified using corresponding mass-spectrometry techniques, were also used to generate comparisons with VaD. Elevated urea levels ranging from 2.2- to 2.4-fold-change in VaD cases were identified in six out of the seven regions analysed. These elevations are similar in magnitude to those observed in uraemic encephalopathy, a CNS disorder characterised by accumulation of urea in the cerebral tissues. Fold-elevation of urea was highest in the basal ganglia and hippocampus (2.4-fold-change), consistent with the observation that these regions are severely affected in VaD. When compared with other age-related dementias, VaD displayed the lowest overall fold-increase, followed by HD (3.4-fold), PDD (4.3-fold), and AD (5.3-fold). Taken together, these data not only describe, for the first time, a multiregional elevation of brain-urea levels in VaD, but also imply the existence of a common urea-mediated disease mechanism that is now known to be present in at least four of the main age-related dementias. If the precise origin of this urea phenotype can be identified, brain-urea metabolism may be a viable target for the experimental treatment of multiple age-related dementias.

Studies of neurodegenerative conditions such as Alzheimer’s disease (AD) using post mortem brain tissues have uncovered several perturbations in metals such as copper, iron, and zinc. However, studies of the effects of key, potentially confounding variables on these tissues are currently lacking. Moreover, human-brain tissues have limited availability, further enhancing the difficulty of matching potentially-significant variables including age, sex-matching, post-mortem delay (PMD), and neuropathological stage. This study aimed to investigate the effects of such factors and how they might influence metal concentrations in post-mortem brains. Cingulate gyrus from AD cases and matched controls was obtained from two brain banks, based in Auckland, New Zealand and Manchester, UK. Inductively-coupled plasma mass spectrometry (ICP-MS) was employed to measure levels of nine essential metals in brain tissues, and compared concentrations between cases and controls, and between cohorts, to analyse effects of age, sex, Braak stage, brain weight, and PMD. The same methods were used to investigate the effects of PMD under more controlled conditions using ex vivo healthy adult rat-brain tissue. Metal concentrations in human brain were found to be unmodified by differences in age, sex-matching, Braak stage, brain weight, and PMD between cohorts. Some metals were, however, found to vary significantly across different regions in rat brains. These results indicate that investigations of metal homeostasis in AD and other neurodegenerative conditions can be reliably performed using brain tissues without confounding by varying PMD, age, sex-matching, brain weight, and Braak stage. However, regions of study should be selected carefully.

Vascular dementia (VaD) is thought to be the second most common cause of age-related dementia amongst the elderly. However, at present, there are no available disease-modifying therapies for VaD, probably due to insufficient understanding about the molecular basis of the disease. While the notion of metal dyshomeostasis in various age-related dementias has gained considerable attention in recent years, there remains little comparable investigation in VaD. To address this evident gap, we employed inductively coupled-plasma mass spectrometry to measure the concentrations of nine essential metals in both dry- and wet-weight hippocampal

Widespread elevations in brain urea have, in recent years, been reported in certain types of age-related dementia, notably Alzheimer’s disease (AD) and Huntington’s disease (HD). Urea increases in these diseases are substantive, and approximate in magnitude to levels present in uraemic encephalopathy. In AD and HD, elevated urea levels are widespread, and not only in regions heavily affected by neurodegeneration. However, measurements of brain urea have not hitherto been reported in Parkinson’s disease dementia (PDD), a condition which shares neuropathological and symptomatic overlap with both AD and HD. Here we report measurements of tissue urea from nine neuropathologically confirmed regions of the brain in PDD and post-mortem delay (PMD)-matched controls, in regions including the cerebellum, motor cortex (MCX), sensory cortex, hippocampus (HP), substantia nigra (SN), middle temporal gyrus (MTG), medulla oblongata (MED), cingulate gyrus, and pons, by applying ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Urea concentrations were found to be substantively elevated in all nine regions, with average increases of 3–4-fold. Urea concentrations were remarkably consistent across regions in both cases and controls, with no clear distinction between regions heavily affected or less severely affected by neuronal loss in PDD. These urea elevations mirror those found in uraemic encephalopathy, where equivalent levels are generally considered to be pathogenic, and those previously reported in AD and HD. Increased urea is a widespread metabolic perturbation in brain metabolism common to PDD, AD, and HD, at levels equal to those seen in uremic encephalopathy. This presents a novel pathogenic mechanism in PDD, which is shared with two other neurodegenerative diseases.

This study aimed at investigating the molecular level organization and photoluminescence in the interlayer space of magadiite (mag) synthesized by the process of solid-state intercalation. Host-guest composites were prepared by an easy grinding process without other operation. Detailed structural investigations were performed by powder X-ray diffraction (XRD), inductively coupled plasma atomic emission spectroscopy (ICP-AES), energy-dispersive X-ray spectrometer (EDS), X-ray photoelectron spectroscopy (XPS), Fourier-transform infrared spectroscopy (FTIR), Thermo-gravimetric analysis and differential thermal analysis (TGA/DTA), field emission scanning electron microscopy (FE-SEM), Ultraviolet-visible spectroscopy (UV–Vis), photoluminescence (PL) and inverted fluorescence microscope. Results confirmed that 8-hydroxyquinoline (8Hq) was intercalated in the interlayer space of mag in the presence of various metal ions (Ca2+, Zn2+ and Mn2+) inside. Basal spacings between silicate layers were controlled by exchanged metal ions and decorated 8Hq. Solid-state intercalation resulted in the lower proportion of intercalated 8Hq, but good luminescence was observed by PL. The complexes in the interlayer space showed special fluorescence properties. A speculative mechanism was proposed for reaction by solid-solid intercalation. This study provided a message for understanding the functional properties of composites 8Hq/Ca, Zn, Mn-mags, such as loading capacity and photoluminescence properties.

Nitrogen is an essential macronutrient for plants and the common limiting factor for crop productivity worldwide. An effective approach to combat N deficiency and overuse is to understand the mechanism of low-nitrogen tolerance in plants and develop low-nitrogen-tolerant crop cultivars. Wild soybean has a high tolerance to poor environmental conditions, but, until now, no study has illustrated the mechanism of low-nitrogen tolerance at a metabolomic level. In this study, the photosynthetic characteristics and metabolomics of wild and cultivated soybean seedlings were analyzed, and the mechanism of wild soybean's low-nitrogen tolerance was explained using a sand culture experiment. Wild soybean was less affected by low-nitrogen stress than cultivated soybean as assessed by plant growth parameters and photosynthesis. The root length of wild soybean increased, and a high root-shoot ratio was maintained under low-nitrogen stress. Carotenoids accumulated, which contributed to its higher low-nitrogen tolerance. A total of 48 and 60 differentially accumulated metabolites were identified in leaves and roots, respectively, between the low-nitrogen stress and control groups. The ability of wild soybean to tolerate low nitrogen also resulted from its capability to enhance the TCA cycle, synthesize key amino acids, accumulate metabolites, such as soluble sugars and organic acids, and synthesize favorable secondary metabolites under low-nitrogen stress. The current results reveal the mechanism underlying wild soybean's high low-nitrogen tolerance and provide the methodology and theoretical basis for utilizing wild soybean, improving cultivated soybean, and studying the low-nitrogen tolerance of other plants.

Experimental in vitro models that accurately capture pathophysiological characteristics of human tumours are essential for basic and translational cancer biology. Here, we describe a fully synthetic hydrogel extracellular matrix, specifically designed to elicit key phenotypic traits of the pancreatic environment in culture. To enable the growth of normal and cancerous pancreatic organoids from murine genetically engineered models and human patients, essential adhesive cues were empirically defined and incorporated into the hydrogel scaffold, revealing a functional role of laminin – integrin a3/a6 signalling in adhesion and survival of pancreatic organoids. Altered tissue stiffness — a hallmark of pancreatic cancer — was recapitulated in culture by adjusting the hydrogel properties to engage mechano-signalling and alter organoid growth. Pancreatic stromal cells were readily incorporated and replicated phenotypic traits characteristic of the tumour environment in vivo. This model therefore recapitulates a pathologically remodelled tumour microenvironment for studies of normal and pancreatic cancer cells in vitro., This upload is compiled of 21 individual data packages which contain the raw data and R-scripts necessary to generate the outputs displayed in the paper. Each folder contains a README document which assists the reader through the files.

Several studies of Parkinson's disease (PD) have reported dysregulation of cerebral metals, particularly decreases in copper and increases in iron in substantia nigra (SN). However, few studies have investigated regions outside the SN, fewer have measured levels of multiple metals across different regions within the same brains, and there are no currently-available reports of metal levels in Parkinson's disease dementia (PDD). This study aimed to compare concentrations of nine essential metals across nine different brain regions in cases of PDD and controls. Investigated were: primary motor cortex (MCX); cingulate gyrus (CG); primary visual cortex (PVC); hippocampus (HP); cerebellar cortex (CB); SN; locus coeruleus (LC); medulla oblongata (MED); and middle temporal gyrus (MTG), thus covering regions with severe, moderate, or low levels of neuronal loss in PDD. Levels of eight essential metals and selenium were determined using an analytical methodology involving the use of inductively-coupled plasma mass spectrometry (ICP-MS), and compared between cases and controls, to better understand the extent and severity of metal perturbations. Findings were also compared with those from our previous study of sporadic Alzheimer's disease dementia (ADD), which employed equivalent methods, to identify differences and similarities between these conditions. Widespread copper decreases occurred in PDD in seven of nine regions (exceptions being LC and CB). Four PDD-affected regions showed similar decreases in ADD: CG, HP, MTG, and MCX. Decreases in potassium and manganese were present in HP, MTG and MCX; decreased manganese was also found in SN and MED. Decreased selenium and magnesium were present in MCX, and decreased zinc in HP. There was no evidence for increased iron in SN or any other region. These results identify alterations in levels of several metals across multiple regions of PDD brain, the commonest being widespread decreases in copper that closely resemble those in ADD, pointing to similar disease mechanisms in both dementias.

Vitamin B5 (d-pantothenic acid; pantothenate) is an essential trace nutrient that functions as the obligate precursor of coenzyme A (CoA), through which it plays key roles in myriad biological processes, including many that regulate carbohydrate, lipid, protein, and nucleic acid metabolism. In the brain, acetyl-CoA is necessary for synthesis of the complex fatty-acyl chains of myelin, and of the neurotransmitter acetylcholine. We recently found that cerebral pantothenate is markedly lowered, averaging ∼55% of control values in cases of Huntington’s disease (HD) including those who are pre-symptomatic, and that regions where pantothenate is lowered correspond to those which are more severely damaged. Here we sought to determine the previously unknown distribution of pantothenate in the normal-rat brain, and whether the diabetic rat might be useful as a model for altered cerebral pantothenate metabolism. We employed histological staining (Nissl) to identify brain structures; immunohistochemistry with anti-pantothenate antibodies to determine the distribution of pantothenate in caudate putamen and cerebellum; and gas-chromatography/mass-spectrometry to quantitate levels of pantothenate and other metabolites in normal- and diabetic-rat brain. Remarkably, cerebral pantothenate was almost entirely localized to myelin-containing structures in both experimental groups. Diabetes did not modify levels or disposition of cerebral pantothenate. These findings are consistent with physiological localization of pantothenate in myelinated white-matter structures, where it could serve to support myelin synthesis. Further investigation of cerebral pantothenate is warranted in neurodegenerative diseases such as HD and Alzheimer’s disease, where myelin loss is a known characteristic of pathogenesis., Highlights • Vitamin B5 (pantothenate) is the obligate precursor of acetyl-coenzyme A (acetyl-CoA). • Acetyl-CoA is essential for the cerebral synthesis of acetylcholine and myelin. • We determined the cerebral disposition of pantothenate in normal and diabetic rats. • Pantothenate was mainly localized to myelin-containing structures in both groups. • Localization of pantothenate to white-matter structures could support cerebral myelin synthesis.

Amorphous manganese silicate/multi-walled carbon nanotubes (AMSi/MWCNTs) composites were successfully synthesized using MWCNTs, manganese dichloride and sodium silicate as the starting materials by a facile precipitation method. The composition and morphology were characterized by X-ray powder diffraction, energy-dispersive X-ray spectrometer, elemental mapping, Raman, Fourier transform infrared spectroscopy, field emission scanning electron microscopy and transmission electron microscopy. Electrochemical properties of AMSi/MWCNTs as supercapacitor electrode were studied. It was found that the electrochemical performance of AMSi could be adjusted by the amount of MWCNTs. Specific capacitance of AMSi/MWCNTs reached the highest value (236 F g−1 at 0.5 A g−1) in the presence of 40 wt.% of MWCNTs. Asymmetric supercapacitor device assembled from AMSi/MWCNTs and activated carbon (AMSi/MWCNTs//AC) showed its specific capacitances reached 146, 139, 119, 108 and 99 F g−1 at current densities of 0.5, 1, 2, 5 and 10 A g−1, respectively. A capacitance retention of 81% for AMSi/MWCNTs//AC device after 1000 cycles indicated that AMSi/MWCNTs had good cycling performance applied to SC device. Present findings demonstrated that MWCNTs could improve the electrochemical properties of AMSi and suggested that AMSi/MWCNTs composites could be considered as potential materials for high-performance energy storage device.

Advance in stem cell research resulted in several processes to generate induced pluripotent stem cells (iPSCs) from adult somatic cells. In our previous study, the reprogramming of iPSCs from human dental mesenchymal stem cells (MSCs) including SCAP and DPSCs, has been reported. Herein, safe iPSCs were reprogrammed from SCAP and DPSCs using non-integrating RNA virus vector, which is an RNA virus carrying no risk of altering host genome. DPSCs- and SCAP-derived iPSCs exhibited the characteristics of the classical morphology with human embryonic stem cells (hESCs) without integration of foreign genes, indicating the potential of their clinical application. Moreover, induced PSCs showed the capacity of self-renewal and differentiation into cardiac myocytes. We have achieved the differentiation of hiPSCs to cardiomyocytes lineage under serum and feeder-free conditions, using a chemically defined medium CDM3. In CDM3, hiPSCs differentiation is highly generating cardiomyocytes. The results showed this protocol produced contractile sheets of up to 97.2% TNNT2 cardiomyocytes after purification. Furthermore, derived hiPSCs differentiated to mature cells of the three embryonic germ layers in vivo and in vitro of beating cardiomyocytes. The above whole protocol enables the generation of large scale of highly pure cardiomyocytes as needed for cellular therapy.

Rainfall infiltration is a key factor that determines the active earth pressure on an earth-retaining structure. Previous investigations on the stability of earth retaining structures were mainly conducted under the assumption that the backfills was dry, saturated, or subjected to a steady unsaturated flow, ignoring the time-varying characteristics of the rainfall infiltration process. Based on the upper bound theorem of limit analysis, this study conducted a stability analysis of a three-dimensional (3D) earth retaining structure (ERS) subjected to various rainfall infiltration patterns. An analytical model that was, capable of calculating the pore water pressure distribution due to rainfall infiltration, was employed to calculate the time-dependent pore water pressure change of unsaturated soil. A horizontal slice method was employed to take into account the change of effective unit weight of soil. Afterward, an analytical expression of the active earth pressure coefficient is derived from the energy balance equation. The effects of the 3D characteristics of ERSs and rainfall patterns on the active earth pressure coefficient and the failure pattern of ERSs were investigated. It was found that compared with plain strain conditions, the 3D characteristics of ERSs lead to a lower value for the active earth pressure and better stability. The rainfall patterns not only directly determined the stability and active earth pressure of an ERS, but also played a dominant role in critical failure pattern of the ERS.

Pantothenic acid (vitamin B5) is an essential trace nutrient required for the synthesis of coenzyme A (CoA). It has previously been shown that pantothenic acid is significantly decreased in multiple brain regions in both Alzheimer’s disease (ADD) and Huntington’s disease (HD). The current investigation aimed to determine whether similar changes are also present in cases of Parkinson’s disease dementia (PDD), another age-related neurodegenerative condition, and whether such perturbations might occur in similar regions in these apparently different diseases. Brain tissue was obtained from nine confirmed cases of PDD and nine controls with a post-mortem delay of 26 h or less. Tissues were acquired from nine regions that show high, moderate, or low levels of neurodegeneration in PDD: the cerebellum, motor cortex, primary visual cortex, hippocampus, substantia nigra, middle temporal gyrus, medulla oblongata, cingulate gyrus, and pons. A targeted ultra–high performance liquid chromatography—tandem mass spectrometry (UHPLC-MS/MS) approach was used to quantify pantothenic acid in these tissues. Pantothenic acid was significantly decreased in the cerebellum (p = 0.008), substantia nigra (p = 0.02), and medulla (p = 0.008) of PDD cases. These findings mirror the significant decreases in the cerebellum of both ADD and HD cases, as well as the substantia nigra, putamen, middle frontal gyrus, and entorhinal cortex of HD cases, and motor cortex, primary visual cortex, hippocampus, middle temporal gyrus, cingulate gyrus, and entorhinal cortex of ADD cases. Taken together, these observations indicate a common but regionally selective disruption of pantothenic acid levels across PDD, ADD, and HD.

Rainfall infiltration is one of the main triggers of slope failure. Based on the upper bound theorem of limit analysis, this work presents an analytical stability analysis of a 3D vertical cut slope subjected to rainfall infiltration. An analytical model that can directly provide pore water pressure change at any depth and time is adopted to calculate the time-dependent matric suction and shear strength of unsaturated soil during the rainfall infiltration process. Thereafter, based on a 3D rotational failure mechanism of a slope, the energy balance equation is built, and the factor of safety (FoS) of the slope is consequently determined in conjunction with the strength reduction technique. The influences of the 3D characteristics of the slope and rainfall patterns on both FoS and failure pattern of the slope are investigated. It is found that the 3D characteristic of slope is a key factor which determines the FoS of slope. Different rainfall infiltration patterns lead to diverse variation rules of both the FoS solutions and the critical failure patterns of slope. However, these rainfall patterns with a same accumulated rainfall result in the same FoS solution of slope at the end of rainfall infiltration. The present work may provide guidance on the stability analysis and preliminary design of slopes subjected to rainfall infiltration.

This paper focuses on the stability of shield tunnel face excavated in nonhomogeneous and anisotropic soils. The models of soil nonhomogeneity and anisotropy are established on basis of existing researches. Two failure mechanisms of tunnel face are constructed to reveal different conditions of face failure. Upper bound analysis is conducted and the analytical solution of supporting pressure is deduced. By virtue of numerical optimization, the upper bound solution of supporting pressure is derived. Parameter analysis shows that both nonhomogeneity and anisotropy of soil mass have great influences on the supporting pressure and corresponding failure mechanism. Besides, the buried depth is also found to be a key factor to the stability of tunnel face.

Background It is critical to study the low nitrogen tolerance in wild soybean with extensive genetic diversity for improving cultivated soybean nitrogen use efficiency. Focusing on plant young and old leaves could provide new insights to low nitrogen tolerance research. This study compared the low nitrogen group with the control group on physiological and metabolomics changes in young and old leaves, respectively, then analyzed and compared the differences of these changes between cultivated and wild soybean. This study aimed to provide a theoretical basis for the molecular mechanism of soybean low nitrogen stress tolerance. Results Wild soybean was less affected by low-nitrogen stress than cultivated soybean as assessed by plant biomass paraments, total carbon content and total nitrogen content. Gas-exchange coefficients and chlorophylls contents maintained relatively stable in wild soybean young leaves, but opposite in cultivated soybean. Wild soybean young leaves also increased the transport of beneficial ions, such as B3+, Fe3+, Mn2+, H2PO4− and C2O42−. In wild soybean old leaves, the nitrogen metabolism pathway was significant enhanced, especially the aspartic acid and GABA metabolisms. While in cultivated soybean, the nitrogen metabolism decreased obviously in young leaves but had no significant change in old leaves. The phenylpropanoid metabolism pathway was also activated in wild soybean. Contrary to cultivated soybeans, wild soybean tricarboxylic acid cycle and carbon metabolism including polyols and organic acids consolidated in old leaves and maintained a relative normal state in young leaves. These strategies could improve the antioxidant and N-fixation capacity in wild soybean. Conclusion The survival and growth of wild soybean under low nitrogen stress conditions relied on physiological adjustments and metabolic changes that occurred at the cellular level. Compared with cultivated soybean, wild soybean young leaves could maintain a relatively normal growth mainly owing to a significant enhancement of key amino acids and nonprotein nitrogen metabolism in old leaves, especially aspartic acid, proline metabolism which provided basis for nitrogen reutilization from old leaves to young leaves. Consolidating the tricarboxylic acid cycle, intensifying phenylpropanoid metabolism, and accumulating more polyols and organic acids also had positive effect on it. Electronic supplementary material The online version of this article (10.1186/s12870-019-2005-6) contains supplementary material, which is available to authorized users.

Huntington&rsquo, s disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat in exon 1 of the HTT gene. HD usually manifests in mid-life with loss of GABAergic projection neurons from the striatum accompanied by progressive atrophy of the putamen followed by other brain regions, but linkages between the genetics and neurodegeneration are not understood. We measured metabolic perturbations in HD-human brain in a case-control study, identifying pervasive lowering of vitamin B5, the obligatory precursor of coenzyme A (CoA) that is essential for normal intermediary metabolism. Cerebral pantothenate deficiency is a newly-identified metabolic defect in human HD that could potentially: (i) impair neuronal CoA biosynthesis, (ii) stimulate polyol-pathway activity, (iii) impair glycolysis and tricarboxylic acid cycle activity, and (iv) modify brain-urea metabolism. Pantothenate deficiency could lead to neurodegeneration/dementia in HD that might be preventable by treatment with vitamin B5.

Total ion current chromatograms of two genotypes soybean seedling leaves extracts obtained from GC-MS. A: W-YL-CK; B: W-YL-LN; C: W-OL-CK; D: W-OL-LN; E: C-YL-CK; F: C-YL-LN; G: C-OL-CK; H: W-OL-LN. (DOCX 1139 kb)

The growth performances in young and old leaves of two soybean varieties under LN stress. C, cultivated soybean; W, wild soybean; CK, control treatment; LN, low nitrogen stress; Up FW, aboveground fresh weight; Up DW, aboveground dry weight; Under FW, underground fresh weight; Under DW, underground dry weight. * and ** indicate significant (P

Tumours are complex ecosystems where phenotypically diverse tumour cells are embedded in a heterocellular environment. Using an in vitro model of intra-tumoural heterogeneity, we find that clonal tumour cell populations establish disparate interactions with stromal fibroblasts to regulate phenotypic diversity across tumour and stromal cell populations. Unexpectedly, tumour sub-clones instruct stromal fibroblasts to acquire distinct phenotypes, thereby increasing fibroblast diversity, whereas tumour cell diversity is reduced by fibroblast interactions. Heterocellular interactions differentially engage tumour cell reciprocal signalling pathways, resulting in normalisation of cell-autonomous differences in MAPK signalling but diversification of AKT signalling. These results demonstrate that tumour-stroma interactions differentially alter tumour and stromal cell diversity and that our existing cell-autonomous perspective on tumour cell heterogeneity underestimates phenotypic diversity.

Huntington's disease (HD) is a genetically-mediated neurodegenerative disorder wherein the aetiological defect is a mutation in the Huntington's gene (HTT), which alters the structure of the huntingtin protein (Htt) through lengthening of its polyglutamine tract, thus initiating a cascade that ultimately leads to premature death. However, neurodegeneration typically manifests in HD only in middle age, and mechanisms linking the causative mutation to brain disease are poorly understood. Brain metabolism is severely perturbed in HD, and some studies have indicated a potential role for mutant Htt as a driver of these metabolic aberrations. Here, our objective was to determine the effects of HD on brain metabolism by measuring levels of polar metabolites in regions known to undergo varying degrees of damage. We performed gas-chromatography/mass spectrometry-based metabolomic analyses in a case-control study of eleven brain regions in short post-mortem-delay human tissue from nine well-characterized HD patients and nine matched controls. In each patient, we measured metabolite content in representative tissue-samples from eleven brain regions that display varying degrees of damage in HD, thus identifying the presence and abundance of 63 different metabolites from several molecular classes, including carbohydrates, amino acids, nucleosides, and neurotransmitters. Robust alterations in regional brain-metabolite abundances were observed in HD patients: these included changes in levels of small molecules that play important roles as intermediates in the tricarboxylic-acid and urea cycles, and amino-acid metabolism. Our findings point to widespread disruption of brain metabolism and indicate a complex phenotype beyond the gradient of neuropathologic damage observed in HD brain.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that currently affects 36 million people worldwide with no effective treatment available. Development of AD follows a distinctive pattern in the brain and is poorly modelled in animals. Therefore, it is vital to widen the spatial scope of the study of AD and prioritise the study of human brains. Here we show that functionally distinct human brain regions display varying and region-specific changes in protein expression. These changes provide insights into the progression of disease, novel AD-related pathways, the presence of a gradient of protein expression change from less to more affected regions and a possibly protective protein expression profile in the cerebellum. This spatial proteomics analysis provides a framework which can underpin current research and open new avenues to enhance molecular understanding of AD pathophysiology, provide new targets for intervention and broaden the conceptual frameworks for future AD research., Jingshu Xu et al. did a comprehensive post-mortem proteomics analysis across six brain regions obtained from Alzheimer’s disease patients and controls. With this spatial proteomics approach, they identified new disease-related pathways and a gradient of protein expression changes that correlates with the pathology of the affected regions.

Sporadic Alzheimer's disease (AD) is a neurodegenerative disorder that causes the most prevalent form of age-related dementia but its pathogenesis remains obscure. Altered regulation of metals, particularly pan-cerebral copper deficiency, and more regionally-localized perturbation of other metals, are prominent in AD brain although data on how these CNS perturbations are reflected in the peripheral bloodstream are inconsistent to date. To assess the potential use of metal dysregulation to generate biomarkers in AD, we performed a case-control study of seven essential metals and selenium, measured by inductively coupled plasma mass-spectrometry, in samples from AD and matched control cases. Metals were sodium, potassium, calcium, magnesium, iron, zinc, and copper. In the whole study-group and in female participants, plasma metal levels did not differ between cases and controls. In males by contrast, there was moderate evidence that zinc levels trended towards increase in AD [10.8 (10.2-11.5)] µmol/L, mean (± 95% CI; P = 0.021) compared with controls [10.2 (9.6-10.4)]. Thus alterations in plasma zinc levels differed between genders in AD. In correlational analysis, there was evidence for an increased number of 'strong' metal co-regulations in AD cases and differential co-modulations of metal pairs: copper-sodium (Rcontrol = - 0.03, RAD = 0.65; P = 0.009), and copper-calcium (Rcontrol = - 0.01, RAD = 0.65; P = 0.01) were significant in AD males, potentially consistent with reported evidence for dysregulation of copper in severely damaged brain regions in AD. In conclusion, our data suggest that the measurement of metals co-regulation in plasma may provide a useful representation of those metal perturbations taking place in the AD brain and therefore might be useful as plasma-based biomarkers.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that currently affects 36 million people worldwide with no effective treatment available. Development of AD follows a distinctive pattern in the brain and is poorly modelled in animals. Therefore, it is vital to widen both the spatial scope of the study of AD and prioritise the study of human brains. Here we show that functionally distinct human brain regions show varying and region-specific changes in protein expression. These changes provide novel insights into the progression of disease, novel AD-related pathways, the presence of a ‘gradient’ of protein expression change from less to more affected regions, and the presence of a ‘protective’ protein expression profile in the cerebellum. This spatial proteomics analysis provides a framework which can underpin current research and opens new avenues of interest to enhance our understanding of molecular pathophysiology of AD, provides new targets for intervention and broadens the conceptual frameworks for future AD research.

Datasets comprising simultaneous measurements of many essential metals in Alzheimer's disease (AD) brain are sparse, and available studies are not entirely in agreement. To further elucidate this matter, we employed inductively-coupled-plasma mass spectrometry to measure post-mortem levels of 8 essential metals and selenium, in 7 brain regions from 9 cases with AD (neuropathological severity Braak IV-VI), and 13 controls who had normal ante-mortem mental function and no evidence of brain disease. Of the regions studied, three undergo severe neuronal damage in AD (hippocampus, entorhinal cortex and middle-temporal gyrus); three are less-severely affected (sensory cortex, motor cortex and cingulate gyrus); and one (cerebellum) is relatively spared. Metal concentrations in the controls differed among brain regions, and AD-associated perturbations in most metals occurred in only a few: regions more severely affected by neurodegeneration generally showed alterations in more metals, and cerebellum displayed a distinctive pattern. By contrast, copper levels were substantively decreased in all AD-brain regions, to 52.8-70.2% of corresponding control values, consistent with pan-cerebral copper deficiency. This copper deficiency could be pathogenic in AD, since levels are lowered to values approximating those in Menkes' disease, an X-linked recessive disorder where brain-copper deficiency is the accepted cause of severe brain damage. Our study reinforces others reporting deficient brain copper in AD, and indicates that interventions aimed at safely and effectively elevating brain copper could provide a new experimental-therapeutic approach.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder that displays pathological characteristics including senile plaques and neurofibrillary tangles. Metabolic defects are also present in AD-brain: for example, signs of deficient cerebral glucose uptake may occur decades before onset of cognitive dysfunction and tissue damage. There have been few systematic studies of the metabolite content of AD human brain, possibly due to scarcity of high-quality brain tissue and/or lack of reliable experimental methodologies. Here we sought to: 1) elucidate the molecular basis of metabolic defects in human AD-brain; and 2) identify endogenous metabolites that might guide new approaches for therapeutic intervention, diagnosis or monitoring of AD. Brains were obtained from nine cases with confirmed clinical/neuropathological AD and nine controls matched for age, sex and post-mortem delay. Metabolite levels were measured in post-mortem tissue from seven regions: three that undergo severe neuronal damage (hippocampus, entorhinal cortex and middle-temporal gyrus); three less severely affected (cingulate gyrus, sensory cortex and motor cortex); and one (cerebellum) that is relatively spared. We report a total of 55 metabolites that were altered in at least one AD-brain region, with different regions showing alterations in between 16 and 33 metabolites. Overall, we detected prominent global alterations in metabolites from several pathways involved in glucose clearance/utilization, the urea cycle, and amino-acid metabolism. The finding that potentially toxigenic molecular perturbations are widespread throughout all brain regions including the cerebellum is consistent with a global brain disease process rather than a localized effect of AD on regional brain metabolism., Highlights • Impaired brain metabolism is a key pathogenic property of sporadic Alzheimer's • 69 altered metabolites were profiled in 7 brain regions in this case–control study. • Severe regulatory defects in energy-producing and amino-acid pathways, and urea • First metabolic profiling study of region-specific alterations in human AD brain • Compelling evidence that sporadic Alzheimer's is a metabolic brain disease

Huntington's disease (HD) is a neurodegenerative disorder wherein the aetiological defect is a mutation in the Huntington's gene (HTT), which alters the structure of the huntingtin protein through the lengthening of a polyglutamine tract and initiates a cascade that ultimately leads to dementia and premature death. However, neurodegeneration typically manifests in HD only in middle age, and processes linking the causative mutation to brain disease are poorly understood. Here, our objective was to elucidate further the processes that cause neurodegeneration in HD, by measuring levels of metabolites in brain regions known to undergo varying degrees of damage. We applied gas-chromatography/mass spectrometry-based metabolomics in a case-control study of eleven brain regions in short post-mortem-delay human tissue from nine well-characterized HD patients and nine controls. Unexpectedly, a single major abnormality was evident in all eleven brain regions studied across the forebrain, midbrain and hindbrain, namely marked elevation of urea, a metabolite formed in the urea cycle by arginase-mediated cleavage of arginine. Urea cycle activity localizes primarily in the liver, where it functions to incorporate protein-derived amine-nitrogen into urea for recycling or urinary excretion. It also occurs in other cell-types, but systemic over-production of urea is not known in HD. These findings are consistent with impaired local urea regulation in brain, by up-regulation of synthesis and/or defective clearance. We hypothesize that defective brain urea metabolism could play a substantive role in the pathogenesis of neurodegeneration, perhaps via defects in osmoregulation or nitrogen metabolism. Brain urea metabolism is therefore a target for generating novel monitoring/imaging strategies and/or therapeutic interventions aimed at ameliorating the impact of HD in patients.

The cholesterol-fed rabbit is commonly used as a model to study the vascular effects of hypercholesterolemia and resulting atherosclerotic lesions. Here we undertook a proteomic case-control investigation of ascending aortas from male New Zealand White rabbits after 10 weeks on a high-cholesterol (2% w/w) diet (HCD, n = 5) or control diet (n = 5), in order to determine the changes in response to the HCD. Histology confirmed intimal thickening in the HCD group consistent with atherosclerosis, and LC-MS/MS analysis of individually-obtained ascending aortic extracts labelled with isobaric (iTRAQ) tags enabled the identification and quantitation of 453 unique proteins above the 1% false discovery rate threshold. Of 67 proteins showing significant differences in relative abundance (p < 0.05), 62 were elevated and five decreased in ascending aortas from HCD-fed rabbits compared to controls. Six proteins were selected for validation using Multiple Reaction Monitoring, which confirmed the iTRAQ results. Many of the observed protein changes are consistent with known molecular perturbations in the ascending aorta that occur in response to hypercholesterolemia, e.g. elevation of tissue levels of apolipoproteins, extracellular matrix adhesion proteins, glycolytic enzymes, heat shock proteins and proteins involved in immune defense. We also made a number of novel observations, including a 15-fold elevation of glycoprotein (trans-membrane) nmb-like (Gpnmb) in response to HCD. Gpnmb has previously been linked to angiogenesis but not to atherosclerosis. This and additional novel observations merit further investigation as these perturbations may play important and as yet undiscovered roles in the pathogenesis of atherosclerosis in rabbits as well as humans.