Involvement of brain oxidation in the cognitive impairment in a triple transgenic mouse model of Alzheimer's disease: Noninvasive measurement of the brain redox state by magnetic resonance imaging

Abstract

Oxidative stress is considered to be related to the onset and/or progression of Alzheimer's disease (AD), but there is insufficient evidence of its role(s). In this study, we evaluated the relationships between the brain redox state and cognitive function using a triple transgenic mouse model of AD (3 × Tg-AD mouse). One group of 3 × Tg-AD mice started to receive an α-tocopherol-supplemented diet at 2 months of age and another group of 3 × Tg-AD mice was fed a normal diet. The levels of α-tocopherol, reduced glutathione, oxidized glutathione, and lipid peroxidation were decreased in the cerebral cortex and hippocampus at 4 months of age in the 3 × Tg-AD mice fed a normal diet. These reductions were abrogated by the supplementation of α-tocopherol in the diet. During Morris water maze testing, the 3 × Tg-AD mice did not exhibit cognitive impairment at 4 months of age, but started to show cognitive dysfunction at 6 months of age, and α-tocopherol supplementation suppressed this dysfunction. Magnetic resonance imaging (MRI) using 3-hydroxymethyl-proxyl as a probe showed decreases in the signal intensity in the brains of 3 × Tg-AD mice at 4 months of age, and this reduction was clearly attenuated by α-tocopherol supplementation. Taken together, these findings suggest that oxidative stress can be associated with the cognitive impairment in 3 × Tg-AD mice. Furthermore, MRI might be a powerful tool to noninvasively evaluate the increases in reactive radicals, especially those occurring during the early stages of AD.     

Evolutionary hypothesis of telomere length in primary breast cancer and brain tumour patients: a tracer for genomic-tumour heterogeneity and instability

It was previously reported that tumour samples had shorter telomeres than the surrounding normal tissue. Hereby, the initial sign of correlation between malignant tissue and telomere behaviour could be noticed. Bridging knowledge between germ and somatic cells could facilitate understanding cellular evolution. The aim of our investigation was to provide evidence for the evolutionary hypothesis of TL (telomere length) in primary BC (breast cancer) and BTs (brain tumours), which might be applied as a prognostic and/or predictive marker. DNA extraction from the frozen tissues was performed using high pure PCR template preparation kit. Standard protocol of Telo TTAGGG Telomere Length Assay kit, a non‐radioactive chemiluminescent assay, was used. The protein expression in extracted cells was analysed by immunofluorescence. We also detected telomerase activity. The G/T (genomic/tumour ratio) for TL in two groups of patients affected with primary BC and primary BT revealed significant differences in both BC patients (P=0.025) and in BTs (P=0.001). The pattern of telomere signals by Q‐FISH (quantitative fluorescent in situ hybridization) show that in all samples, except one, SI (signal intensity) has been significantly decreased in tissue related to blood, either in BC patients or in patients with BTs (0.041≥P≥0.001). However, the data achieved by Q‐FISH support the results of Southern blot. These data reflect a significant diversity either in BC or in BT patients, providing evidence for the evolutionary hypothesis of TL in cancer development and progression.     

Role of transferrin in iron uptake by the brain: a comparative study

Summary The role of specific transferrin (Tf) and Tf receptor interaction on brain capillary endothelial cells in iron transport from the plasma to the brain was investigated by using Tf from several species of animals labeled with ⁵⁹Fe and ¹²⁵I, and 15-day and adult rats. The rate of iron transfer was much greater in the 15-day rats. It was greatest with Tf from the mammals, rat, rabbit and human, but much lower with chicken ovotransferrin and quokka (a marsupial), toad, lizard, crocodile, and fish Tf. The uptake of Tf by the brain showed a similar pattern, except for a very high uptake of ovotransferrin (ovo Tf). Iron uptake by the femurs (a source of bone marrow) was also high with Tf from the mammalian species and low with the other types of Tf, but showed little change with aging of the animals. It is concluded that iron transport into the brain is dependent on the function of Tf receptors, probably on capillary endothelial cells, and that these receptors show the same type of species specificity as the receptors on immature erythroid cells. Also, the decrease in iron uptake by the brain as rats age from 15 days to adulthood is specific for the brain and is not a general effect of the aging process.Abbreviations Tf transferrin - ovo Tf ovotransferrin     

The epigenetic component of the brain response to electromagnetic stimulation in Parkinson's Disease patients: A literature overview

Modulations of epigenetic machinery, namely DNA methylation pattern, histone modification, and non‐coding RNAs expression, have been recently included among the key determinants contributing to Parkinson's Disease (PD) aetiopathogenesis and response to therapy. Along this line of reasoning, a set of experimental findings are highlighting the epigenetic‐based response to electromagnetic (EM) therapies used to alleviate PD symptomatology, mainly Deep Brain Stimulation (DBS) and Transcranial Magnetic Stimulation (TMS). Notwithstanding the proven efficacy of EM therapies, the precise molecular mechanisms underlying the brain response to these types of stimulations are still far from being elucidated. In this review we provide an overview of the epigenetic changes triggered by DBS and TMS in both PD patients and neurons from different experimental animal models. Furthermore, we also propose a critical overview of the exposure modalities currently applied, in order to evaluate the technical robustness and dosimetric control of the stimulation, which are key issues to be carefully assessed when new molecular findings emerge from experimental studies. Bioelectromagnetics. 39:3–14, 2018. © 2017 Wiley Periodicals, Inc.     

IgG‐single chain Fv fusion protein therapeutic for alzheimer's disease: Expression in CHO cells and pharmacokinetics and brain delivery in the rhesus monkey

Monoclonal antibodies (MAb) directed against the Abeta amyloid peptide of Alzheimer's disease (AD) are potential new therapies for AD, since these antibodies disaggregate brain amyloid plaque. However, the MAb is not transported across the blood–brain barrier (BBB). To enable BBB transport, a single chain Fv (ScFv) antibody against the Abeta peptide of AD was re‐engineered as a fusion protein with the MAb against the human insulin receptor (HIR). The HIRMAb acts as a molecular Trojan horse to ferry the ScFv therapeutic antibody across the BBB. Chinese hamster ovary (CHO) cells were stably transfected with a tandem vector encoding the heavy and light chains of the HIRMAb–ScFv fusion protein. A high secreting line was isolated following methotrexate amplification and dilutional cloning. The HIRMAb–ScFv fusion protein in conditioned serum‐free medium was purified by protein A affinity chromatography. The fusion protein was stable as a liquid formulation, and retained high‐affinity binding of both the HIR and the Abeta amyloid peptide. The HIRMAb–ScFv fusion protein was radiolabeled with the ¹²⁵I‐Bolton–Hunter reagent, followed by measurement of the pharmacokinetics of plasma clearance and brain uptake in the adult Rhesus monkey. The HIRMAb–ScFv fusion protein was rapidly cleared from plasma and was transported across the primate BBB in vivo. In conclusion, the HIRMAb–ScFv fusion protein is a new class of antibody‐based therapeutic for AD that has been specifically engineered to cross the human BBB. Biotechnol. Bioeng. 2010; 105: 627–635. © 2009 Wiley Periodicals, Inc.     

Dolphin social intelligence: complex alliance relationships in bottlenose dolphins and a consideration of selective environments for extreme brain size evolution in mammals

Bottlenose dolphins in Shark Bay, Australia, live in a large, unbounded society with a fission-fusion grouping pattern. Potential cognitive demands include the need to develop social strategies involving the recognition of a large number of individuals and their relationships with others. Patterns of alliance affiliation among males may be more complex than are currently known for any non-human, with individuals participating in 2-3 levels of shifting alliances. Males mediate alliance relationships with gentle contact behaviours such as petting, but synchrony also plays an important role in affiliative interactions. In general, selection for social intelligence in the context of shifting alliances will depend on the extent to which there are strategic options and risk. Extreme brain size evolution may have occurred more than once in the toothed whales, reaching peaks in the dolphin family and the sperm whale. All three 'peaks' of large brain size evolution in mammals (odontocetes, humans and elephants) shared a common selective environment: extreme mutual dependence based on external threats from predators or conspecific groups. In this context, social competition, and consequently selection for greater cognitive abilities and large brain size, was intense.     

Size matters for lice on birds: Coevolutionary allometry of host and parasite body size

Body size is one of the most fundamental characteristics of all organisms. It influences physiology, morphology, behavior, and even interspecific interactions such as those between parasites and their hosts. Host body size influences the magnitude and variability of parasite size according to Harrison's rule (HR: positive relationship between host and parasite body sizes) and Poulin's Increasing Variance Hypothesis (PIVH: positive relationship between host body size and the variability of parasite body size). We analyzed parasite–host body size allometry for 581 species of avian lice (～15% of known diversity) and their hosts. We applied phylogenetic generalized least squares (PGLS) methods to account for phylogenetic nonindependence controlling for host and parasite phylogenies separately and variance heterogeneity. We tested HR and PIVH for the major families of avian lice (Ricinidae, Menoponidae, Philopteridae), and for distinct ecological guilds within Philopteridae. Our data indicate that most families and guilds of avian lice follow both HR and PIVH; however, ricinids did not follow PIVH and the “body lice” guild of philopterid lice did not follow HR or PIVH. We discuss mathematical and ecological factors that may be responsible for these patterns, and we discuss the potential pervasiveness of these relationships among all parasites on Earth.     

Degradation of met-enkephalin by extracts of various regions of the human brain: effects of antipsychotics and narcotics in vitro

Antischizophrenic drugs, reduced in a concentration-dependent fashion enkephalin degradation by the soluble and particulate fractions of the human cerebral cortex and cerebellum. The order of potency is as follows: thioridazine greater than chlorpromazine greater than fluphenazine greater than haloperidol greater than or equal to promazine with IC50 of 50, 80, 120, 200-250 micro M, respectively. Kinetic studies revealed non-competitive and competitive inhibition by thioridazine and chlorpromizine, respectively. Narcotics, were weak inhibitors of enkephalin degradation. For dl-, d-, l-methadone and l-alpha-acetylmethadol, IC50 was about 500 micro M, and 1000 micro M for heroin and morphine. It is suggested that inhibition of the degradation of endogenous morphinomimetic peptides in the CNS may be a crucial factor governing the pharmacology of some neuroleptics and other psychoactive drugs. Enkephalin-hydrolyzing activity was ubiquitous and exhibited considerable regional differences in the normal human and in Huntington's chorea brains. The rate of enkephalin degradation is generally higher in the subcortical nuclei than in the cortex and cerebellum. The highest hydrolytic activity was found in the substantia nigra, anterior thalamus, septal area, globus pallidus and caudate nucleus, in this decreasing order.     

Space use and social association in a gregarious ungulate: Testing the conspecific attraction and resource dispersion hypotheses

Animals use a variety of proximate cues to assess habitat quality when resources vary spatiotemporally. Two nonmutually exclusive strategies to assess habitat quality involve either direct assessment of landscape features or observation of social cues from conspecifics as a form of information transfer about forage resources. The conspecific attraction hypothesis proposes that individual space use is dependent on the distribution of conspecifics rather than the location of resource patches, whereas the resource dispersion hypothesis proposes that individual space use and social association are driven by the abundance and distribution of resources. We tested the conspecific attraction and the resource dispersion hypotheses as two nonmutually exclusive hypotheses explaining social association and of adult female caribou (Rangifer tarandus). We used location data from GPS collars to estimate interannual site fidelity and networks representing home range overlap and social associations among individual caribou. We found that home range overlap and social associations were correlated with resource distribution in summer and conspecific attraction in winter. In summer, when resources were distributed relatively homogeneously, interannual site fidelity was high and home range overlap and social associations were low. Conversely, in winter when resources were distributed relatively heterogeneously, interannual site fidelity was low and home range overlap and social associations were high. As access to resources changes across seasons, caribou appear to alter social behavior and space use. In summer, caribou may use cues associated with the distribution of forage, and in winter caribou may use cues from conspecifics to access forage. Our results have broad implications for our understanding of caribou socioecology, suggesting that caribou use season‐specific strategies to locate forage. Caribou populations continue to decline globally, and our finding that conspecific attraction is likely related to access to forage suggests that further fragmentation of caribou habitat could limit social association among caribou, particularly in winter when access to resources may be limited.     

High levels of brain dolichols in neuronal ceroid-lipofuscinosis and senescence

Dolichols as unesterified alcohols were identified as significant components of lipid extracts from storage cytosomes isolated post-mortem from the brains of patients with the infantile, late infantile, and juvenile types of neuronal ceroid-lipofuscinosis (NCL). Very small amounts of dolichols were present in the corresponding subcellular fractions of non-NCL brains. The nuclear fraction from NCL cerebral cortex contained the highest dolichol content expressed per milligram protein or lipid, whereas the crude mitochondrial fraction was the richest in normal brain. Highly significant elevations of dolichol levels were found in human cerebral cortex of patients with NCL and Alzheimer's disease compared with age-matched controls, but the levels were normal in Pick's disease. In human non-NCL cerebral cortex, dolichols increased from 16 micrograms/g at age 5 to over 200 at age 81. Rat cerebral cortex showed a similar progressive increase in dolichol content with age. The high dolichol values in NCL, Alzheimer's disease, and senescence appears to be related to the increase of lipofuscin in brain. This is the first time a uniform biochemical abnormality has been found in all childhood forms of NCL, but the enzyme defect is still unidentified. It may lie on pathways where dolichols and retinyl compounds are recycled in Golgi membranes and derived organelles during the biosynthesis of glycoproteins.     

Origin of the 1918 Spanish influenza virus: a comparative genomic analysis

To test the avian-origin hypothesis of the 1918 Spanish influenza virus we surveyed influenza sequences from a broad taxonomic distribution and collected 65 full-length genomes representing avian, human and "classic" swine H1N1 lineages in addition to numerous other swine (H1N2, H3N1, and H3N2), human (H2N2, H3N2, and H5N1), and avian (H1N1, H4N6, H5N1, H6N1, H6N6, H6N8, H7N3, H8N4, H9N2, and H13N2) subtypes. Amino acids from all eight segments were concatenated, aligned, and used for phylogenetic analyses. In addition, the genes of the polymerase complex (PB1, PB2, and PA) were analyzed individually. All of our results showed the Brevig-Mission/1918 strain in a position basal to the rest of the clade containing human H1N1s and were consistent with a reassortment hypothesis for the origin of the 1918 virus. Our genome phylogeny further indicates a sister relationship with the "classic" swine H1N1 lineage. The individual PB1, PB2, and PA phylogenies were consistent with reassortment/recombination hypotheses for these genes. These results demonstrate the importance of using a complete-genome approach for addressing the avian-origin hypothesis and predicting the emergence of new pandemic influenza strains.     

Brains and bravery: Little evidence of a relationship between brain size and flightiness in shorebirds

The ability of birds to perceive, assess and appropriately respond to the presence of relatively novel threats is important to their survival. We hypothesized that the cognitive capacity of birds will influence their ability for accurate response to novelty. We used brain volume as a surrogate for cognitive capacity and postulated that larger brained birds would moderate their responses when presented with a benign, frequently occurring stimulus, such as a person, because they would habituate more readily. We conducted phylogenetic generalized least square regression to investigate the relationship between brain volume and flight initiation distance (FID; the distance to which a bird can be approached before initiating escape behaviour), while controlling for confounding factors including body size (body mass and wing length) and migration status. We compared seven different models using combinations of these parameters using Akaike's information criterion to determine the best approximating model(s) explaining FID. The two best‐supported models included only wing length and only body mass with Akaike weights of 0.396 and 0.311 respectively. No model including brain volume had an Akaike weight greater than 0.083 and brain volume was poorly correlated with FID in models after controlling for body mass. Thus, brain volume does not appear to strongly relate to bravery among these shorebirds.     

Four methods for general anaesthesia in the rabbit: a comparative study

The efficacy and safety of pentobarbitone, ketamine/xylazine, fentanyl/fluanisone/diazepam, and halothane/nitrous oxide anaesthesia were compared in 4 groups of six New Zealand White rabbits. Heart and respiratory rates, body temperature, reflexes, blood pressure and blood gases were measured. Pentobarbitone appeared to be unsuitable for anaesthesia in rabbits, as 5 of the 6 rabbits to whom it was administered, required artificial respiration or died. The combinations of ketamine/xylazine and fentanyl-fluanisone/diazepam both produced unpredictable levels of anaesthesia together with a substantial decline in arterial blood pressure and PO2. Despite a severe drop in blood pressure (up to 37.5%), anaesthesia with halothane and nitrous oxide was found to be superior to the other anaesthetic agents.     

Challenges and pitfalls in the characterization of anonymous outlier AFLP markers in non-model species: lessons from an ocellated lizard genome scan

In the last few years, dozens of studies have documented the detection of loci influenced by selection from genome scans in a wide range of non-model species. Many of those studies used amplified fragment length polymorphism (AFLP) markers, which became popular for being easily applicable to any organism. However, because they are anonymous markers, AFLPs impose many challenges for their isolation and identification. Most recent AFLP genome scans used capillary electrophoresis (CE), which adds even more obstacles to the isolation of bands with a specific size for sequencing. These caveats might explain the extremely low number of studies that moved from the detection of outlier AFLP markers to their actual isolation and characterization. We document our efforts to characterize a set of outlier AFLP markers from a previous genome scan with CE in ocellated lizards (Lacerta lepida). Seven outliers were successfully isolated, cloned and sequenced. Their sequences are noncoding and show internal indels or polymorphic repetitive elements (microsatellites). Three outliers were converted into codominant markers by using specific internal primers to sequence and screen population variability from undigested DNA. Amplification in closely related lizard species was also achieved, revealing remarkable interspecific conservation in outlier loci sequences. We stress the importance of following up AFLP genome scans to validate selection signatures of outlier loci, but also report the main challenges and pitfalls that may be faced during the process.     

Cooperation and the evolution of intelligence

The high levels of intelligence seen in humans, other primates, certain cetaceans and birds remain a major puzzle for evolutionary biologists, anthropologists and psychologists. It has long been held that social interactions provide the selection pressures necessary for the evolution of advanced cognitive abilities (the 'social intelligence hypothesis'), and in recent years decision-making in the context of cooperative social interactions has been conjectured to be of particular importance. Here we use an artificial neural network model to show that selection for efficient decision-making in cooperative dilemmas can give rise to selection pressures for greater cognitive abilities, and that intelligent strategies can themselves select for greater intelligence, leading to a Machiavellian arms race. Our results provide mechanistic support for the social intelligence hypothesis, highlight the potential importance of cooperative behaviour in the evolution of intelligence and may help us to explain the distribution of cooperation with intelligence across taxa.     

The importance of phylogenetic scale in tests of Bergmann's and Rapoport's rules: lessons from a clade of South American lizards

We tested for the occurrence of Bergmann's rule, the pattern of increasing body size with latitude, and Rapoport's rule, the positive relationship between geographical range size and latitude, in 34 lineages of Liolaemus lizards that occupy arid regions of the Andean foothills. We tested the climatic-variability hypothesis (CVH) by examining the relationship between thermal tolerance breadth and distribution. Each of these analyses was performed varying the level of phylogenetic inclusiveness. Bergmann's rule and the CVH were supported, but Rapoport's rule was not. More variance in the data for Bergmann's rule and the CVH was explained using species belonging to the L. boulengeri series rather than all species, and inclusion of multiple outgroups tended to obscure these macroecological patterns. Evidence for Bergmann's rule and the predicted patterns from the CVH remained after application of phylogenetic comparative methods, indicating a greater role of ecological processes rather than phylogeny in shaping the current species distributions of these lizards.     

phorest: a web‐based tool for comparative analyses of expressed sequence tag data

Comparative analysis of expressed sequence tags is becoming an important tool in molecular ecology for comparing gene expression in organisms grown in certain environments. Additionally, expressed sequence tag database information can be used for the construction of DNA microarrays and for the detection of single nucleotide polymorphisms. For such applications, we present phorest , a web‐based tool for managing, analysing and comparing various collections of expressed sequence tags. It is written in PHP (PHP: Hypertext Preprocessor) and runs on UNIX, Microsoft Windows and Macintosh (Mac OS X) platforms.     

Mate fidelity and coloniality in waterbirds: a comparative analysis

Increased opportunities for information are one potential benefit of sociality. We apply this idea to the advantages of colonial breeding in bird species that are typically monogamous within a breeding season but often form new pair-bonds in subsequent seasons. Individuals may benefit from nesting in colonies at high density by identifying good-quality potential alternative mates among their neighbours. The opportunities for finding a better mating option are likely to increase with colony size and density. We tested this prediction with a comparative analysis of the association between mate fidelity and coloniality in waterbirds (wading birds and seabirds), where there is wide variation in both the degree of mate retention over consecutive breeding seasons and the degree of coloniality. We used two comparative statistical analyses, one based upon generalized least squares and the other based upon a continuous-time Markov model, to test whether the pattern of association between divorce rate and degree of coloniality was evidence for correlated evolutionary change in the two characters. We found a significant and positive association between divorce rate and the degree of coloniality in waterbirds. The probable ancestral state corresponds to a combination of a high degree of coloniality with no, or weak, mate fidelity. The reconstruction of the historical pattern of character origin and evolution indicates that the transition from a high to a low degree of coloniality occurred before the transition to higher mate fidelity. Received: 5 January 1998 / Accepted: 20 April 1998