Understanding neurodegeneration : a neuropathologist’s perspective

A.1.1 Our initial studies, published in Brain and Acta Neuropathologica aimed to extend our knowledge about the British pedigree and to understand the neuropathology of this condition (Ref: 1 current citations: 119; Ref: 2 current citations: 52; Ref: 3 current citations: 73). A.1.2 In 1999 and 2000 our joint research led to the discovery of the causes of the two diseases, which we re-named familial British dementia (FBD) and familial Danish dementia (FDD). In these studies, we showed that both FBD and FDD are associated with unique mutations in the novel BRI2 gene. Our paper which dealt with the British condition was published in Nature (Ref: 4 current citations: 322) while the study about the Danish pedigree was published in the Proceedings of the National Academy of Science, USA (Ref: 5 current citations: 224). In these two seminal studies, we showed that by abolishing the normal stop codon, both mutations (a Stop-to-Arg point mutation in the British pedigree, and a 10-nucleotide insertion mutation in the Danish kindred) result in elongation of the BRI precursor protein. Furin-like processing of the mutated precursor proteins releases the novel, 34 amino acid-long amyloid peptides, ABri in FBD and ADan in FDD, which are different from one another in their 12 C-terminal amino acids. A.1.3 The discovery of the causes of the two diseases triggered several further, biochemical and neuropathological studies (Refs: 6-14). Among others, we were the first, who were able to study with our newly generated antibodies specific to either ABri or ADan, the cerebral distribution of the ABri and ADan deposits in FBD and FDD cases, respectively. Among the many novel findings, our studies demonstrated that, as in Alzheimer’ disease, in both FBD and FDD there are amyloid plaques, cerebral amyloid angiopathy and neurofibrillary tangles, despite the fact that there is no similarity between the Alzheimer disease’s amyloid- peptide and the two closely related amyloid peptides, ABri and ADan, indicating a general link between cerebral amyloid formation and neurofibrillary degeneration. We also showed that, as in Alzheimer’s disease, the neurofibrillary tangles are composed of both major classes of the tau isoforms and that ultrastructurally the tau filaments forming neurofibrillary tangles are classical paired helical filaments in both FBD and FDD (Ref: 6 current citations: 94; Ref: 7 current citations: 86). ..

Impacts of energy taxation in the enlarged European Union, evaluation with GEM-E3 Europe

The objective of this study is twofold: first to analyze how the implementation of the EU energy tax policies will affect the EU and its Member States and secondly to analyze how energy tax policies can contribute to climate policy objectives in the enlarged EU.European Union, taxation, environment

Garlic compounds selectively kill childhood pre-B acute lymphoblastic leukemia cells in vitro without reducing T-cell function: Potential therapeutic use in the treatment of ALL

Drugs used for remission induction therapy for childhood precursor-B acute lymphoblastic leukemia (ALL) are nonselective for malignant cells. Several garlic compounds have been shown to induce apoptosis of cancer cells and to alter lymphocyte function. To investigate the effect of garlic on the apoptosis of ALL cells and lymphocyte immune function, cells from newly diagnosed childhood ALL patients were cultured with several commonly used chemotherapeutic agents and several garlic compounds. Apoptosis, lymphocyte proliferation and T-cell cytokine production were determined using multiparameter flow cytometry. At concentrations of garlic compounds that did not result in significant increases in Annexin V and 7-AAD staining of normal lymphocytes, there was a significant increase in apoptosis of ALL cells with no alteration of T-cell proliferation as determined by CD25/CD69 upregulation or interferonγ, interleukin-2 or tumor necrosis factor-α intracellular cytokine production. In contrast, the presence of chemotherapeutic agents resulted in nonselective increases in both lymphocyte and ALL apoptosis and a decrease in T-cell proliferation and cytokine production. In conclusion, we show selective apoptosis of malignant cells by garlic compounds that do not alter T-cell immune function and indicate the potential therapeutic benefit of garlic compounds in the treatment of childhood ALL

Association of clusterin with the BRI2-derived amyloid molecules ABri and ADan

Familial British and Danish dementias (FBD and FDD) share striking neuropathological similarities with Alzheimer's disease (AD), including intraneuronal neurofibrillary tangles as well as parenchymal and vascular amyloid deposits. Multiple amyloid associated proteins with still controversial role in amyloidogenesis colocalize with the structurally different amyloid peptides ABri in FBD, ADan in FDD, and Aβ in AD. Genetic variants and plasma levels of one of these associated proteins, clusterin, have been identified as risk factors for AD. Clusterin is known to bind soluble Aβ in biological fluids, facilitate its brain clearance, and prevent its aggregation. The current work identifies clusterin as the major ABri- and ADan-binding protein and provides insight into the biochemical mechanisms leading to the association of clusterin with ABri and ADan deposits. Mirroring findings in AD, the studies corroborate clusterin co-localization with cerebral parenchymal and vascular amyloid deposits in both disorders. Ligand affinity chromatography with downstream Western blot and amino acid sequence analyses unequivocally identified clusterin as the major ABri- and ADan-binding plasma protein. ELISA highlighted a specific saturable binding of clusterin to ABri and ADan with low nanomolar Kd values within the same range as those previously demonstrated for the clusterin-Aβ interaction. Consistent with its chaperone activity, thioflavin T binding assays clearly showed a modulatory effect of clusterin on ABri and ADan aggregation/fibrillization properties. Our findings, together with the known multifunctional activity of clusterin and its modulatory activity on the complex cellular pathways leading to oxidative stress, mitochondrial dysfunction, and the induction of cell death mechanisms - all known pathogenic features of these protein folding disorders - suggests the likelihood of a more complex role and a translational potential for the apolipoprotein in the amelioration/prevention of these pathogenic mechanisms.This work was supported by grants from the National Institutes of Health NS051715 (to AR) and AG030539, AG051266, AG059695, and AG065651 (to JG) and from CIBERNED and the Spanish Ministry of Science (SAF2016-78603-R and PID2019-110401RB-I00) and Institutional grants from the Queen Sofia Foundation, CIEN Foundation and the Carlos III Institutes of Health (to MC). TL is supported by an Alzheimer's Research UK senior fellowship. TR is supported by a grant from the Karin & Sten Mortstedt CBD Solutions AB, Stockholm, Sweden and by the National Institute for Health Research (NIHR) Queen Square Biomedical Research Unit in Dementia based at University College London Hospitals (UCLH), University College London (UCL). The views expressed are those of the authors and not necessarily those of the NIH, NHS, the NIHR or the Department of Health.S

Globular glial tauopathy type II

The globular glial tauopathies (GGTs) are a rare group of neurodegenerative diseases with fewer than 90 autopsy-confirmed cases reported in the literature. Although there has been some uncertainty about whether GGT is entirely distinct from progressive supranuclear palsy, a recent study of tau filament structures supports the definition of GGT as a separate neuropathological entity. We present a sporadic case of GGT type II presenting with a progressive corticobasal-primary lateral sclerosis overlap syndrome in a 74-year-old woman. Neuropathological examination identified neuronal and glial tau inclusions, including globular astrocytic and oligodendroglial inclusions. We also discuss the clinical features and molecular pathophysiology of GGT. Increased awareness of this condition could become more important as patients with GGT may be candidates for anti-tau therapies currently undergoing clinical evaluation in patients with other tauopathies

GEM-E3 Model Documentation

The computable general equilibrium model GEM-E3 has been used in a large set of climate policy applications supporting Commission policy proposals during the last decade, as well as in other environmental and economic policy areas. It can be considered a multi-purpose macroeconomic model, designed to estimate the effects of sector-specific policies on the economy as a whole. The main purpose of this publication is to provide extensive documentation of the model's equations and its underlying databases, in order to offer to the broader audience an accurate description of the model characteristics.JRC.J.1-Economics of Climate Change, Energy and Transpor

Landscape-scale connectivity and fragment size determine species composition of grassland fragments

As a consequence of agricultural intensification and habitat fragmentation since the mid-20th century, biological diversity has declined considerably throughout the world, particularly in Europe. We assessed how habitat and landscape-scale heterogeneity, such as variation in fragment size (small vs. large) and landscape configuration (measured as connectivity index), affect plant and arthropod diversity. We focused on arthropods with different feeding behaviour and mobility, spiders (predators, moderate dispersal), true bugs (mainly herbivores and omnivores with moderate dispersal), wild bees (pollinators with good dispersal abilities), and wasps (pollinators, omnivores with good dispersal abilities). We studied 60 dry grassland fragments in the same region (Hungarian Great Plain); 30 fragments were represented by the grassland component of forest-steppe stands, and 30 were situated on burial mounds (kurgans). Forest-steppes are mosaics of dry grasslands with small forests in a matrix of plantation forests. Kurgans are ancient burial mounds with moderately disturbed grasslands surrounded by agricultural fields. The size of fragments ranged between 0.16 6.88 ha (small: 0.16 0.48 ha, large: 0.93 6.88 ha) for forest-steppes and 0.01 0.44 ha (small: 0.01 0.10 ha and large: 0.20 0.44 ha) for kurgans. Fragments also represented an isolation gradient from almost cleared and homogenous landscapes, to landscapes with relatively high compositional heterogeneity. Fragment size, connectivity, and their interaction affected specialist and generalist species abundances of forest-steppes and kurgans. Large fragments had higher species richness of ground-dwelling spiders, and the effect of connectivity was more strongly positive for specialist arthropods and more strongly negative for generalists in large than in small fragments. However, we also found a strong positive impact of connectivity for generalist plants in small kurgans in contrast to larger ones. We conclude that besides the well-known effect of enhancing habitat quality, increasing connectivity between fragments by restoring natural and semi-natural habitat patches would help to maintain grassland biodiversityinfo:eu-repo/semantics/publishedVersio

The novel MAPT mutation K298E:mechanisms of mutant tau toxicity, brain pathology and tau expression in induced fibroblast-derived neurons

Frontotemporal lobar degeneration (FTLD) consists of a group of neurodegenerative diseases characterized by behavioural and executive impairment, language disorders and motor dysfunction. About 20-30 % of cases are inherited in a dominant manner. Mutations in the microtubule-associated protein tau gene (MAPT) cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T). Here we report a novel MAPT mutation (K298E) in exon 10 in a patient with FTDP-17T. Neuropathological studies of post-mortem brain showed widespread neuronal loss and gliosis and abundant deposition of hyperphosphorylated tau in neurons and glia. Molecular studies demonstrated that the K298E mutation affects both protein function and alternative mRNA splicing. Fibroblasts from a skin biopsy of the proband taken at post-mortem were directly induced into neurons (iNs) and expressed both 3-repeat and 4-repeat tau isoforms. As well as contributing new knowledge on MAPT mutations in FTDP-17T, this is the first example of the successful generation of iNs from skin cells retrieved post-mortem

MAPT-Associated Familial Progressive Supranuclear Palsy with Typical Corticobasal Degeneration Neuropathology: A Clinicopathological Report

Corticobasal degeneration (CBD) is a rare, 4-repeat (4R) tauopathy characterized by astrocytic plaque neuropathology. Although ~25% of sporadic CBD cases present with progressive supranuclear palsy-Richardson's syndrome (PSP-RS),1 only one other case of microtubule-associated protein tau gene (MAPT)- related CBD with a PSP-like phenotype has been reported.2 We aim to highlight important issues regarding the classification of MAPT-associated tauopathies and the implications for clinical research