Publications by authors named "Pol Andrés-Benito"

36 Publications

Transcriptional Signatures of Synaptic Vesicle Genes Define Myotonic Dystrophy Type I Neurodegeneration.

Neuropathol Appl Neurobiol 2021 May 5. Epub 2021 May 5.

Computational Neuroimaging Group, Biocruces-Bizkaia Health Research Institute, Barakaldo, Spain.

Aim: To delineate the neurogenetic profiles of brain degeneration patterns in Myotonic Dystrophy Type I (DM1).

Methods: In two cohorts of DM1 patients, brain maps of volume loss (VL) and neuropsychological deficits (ND) were intersected to large-scale transcriptome maps provided by the Allen Human Brain Atlas (AHBA). For validation, neuropathological and RNA analyses were performed in a small series of DM1 brain samples.

Results: Two-fold: 1. From a list of preselected hypothesis-driven genes, confirmatory analyses found that three genes play a major role in brain degeneration: dystrophin (DMD), alpha-synuclein (SNCA) and the microtubule-associated protein tau (MAPT). Neuropathological analyses confirmed a highly heterogeneous Tau-pathology in DM1, different to the one in Alzheimer's disease. 2. Exploratory analyses revealed gene clusters enriched for key biological processes in the central nervous system, such as synaptic vesicle recycling, localization, endocytosis and exocytosis, and the serotonin and dopamine neurotransmitter pathways. RNA analyses confirmed synaptic vesicle dysfunction.

Conclusions: The combination of large-scale transcriptome interactions with brain imaging and cognitive function sheds light on the neurobiological mechanisms of brain degeneration in DM1, that might help define future therapeutic strategies and research into this condition.
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http://dx.doi.org/10.1111/nan.12725DOI Listing
May 2021

Nuclear lipidome is altered in amyotrophic lateral sclerosis: a pilot study.

J Neurochem 2021 Apr 27. Epub 2021 Apr 27.

Department of Experimental Medicine, School of Medicine, IRBLleida-UdL, Avda Rovira Roure 80 25196, Lleida, Spain.

Nucleocytosolic transport, a membrane process, is impaired in motor neurons in amyotrophic lateral sclerosis (ALS). This study analyzes the nuclear lipidome in motor neurons in ALS, and examines molecular pathways linked to the major lipid alterations. Nuclei were obtained from the frozen anterior horn of the lumbar spinal cord of ALS patients and age-matched controls. Lipidomic profiles of this subcellular fraction were obtained using liquid chromatography and mass spectrometry. We validated the mechanisms behind presumable lipidomic changes by exploring ALS surrogate models including human motor neurons (derived from ALS lines and controls) subjected to oxidative stress, the hSOD-G93A transgenic mice, and samples from an independent cohort of ALS patients. Among the differential lipid species, we noted 41 potential identities, mostly belonging to phospholipids (particularly ether phospholipids, as plasmalogens), as well as diacylglycerols and triacylglycerides. Decreased expression of alkyldihydroxyacetonephosphate synthase (AGPS)-a critical peroxisomal enzyme in plasmalogen synthesis-is found in motor neuron disease models; this occurs in parallel with an increase in the expression of sterol carrier protein 2 (SCP2) mRNA in ALS and Scp2 levels in G93A transgenic mice. Further, we identified diminished expression of diacylglycerol-related enzymes, such as phospholipase C βI (PLCβI) and protein kinase CβII (PKCβII), linked to diacylglycerol metabolism. Finally, lipid droplets were recognized in the nuclei, supporting the identification of triacylglycerides as differential lipids. Our results point to the potentially pathogenic role of altered composition of nuclear membrane lipids and lipids in the nucleoplasm in the anterior horn of the spinal cord in ALS. Overall, these data support the usefulness of subcellular lipidomics applied to neurodegenerative diseases.
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http://dx.doi.org/10.1111/jnc.15373DOI Listing
April 2021

TREM2 expression in the brain and biological fluids in prion diseases.

Acta Neuropathol 2021 Apr 21. Epub 2021 Apr 21.

Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), L'Hospitalet de Llobregat, Spain.

Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune cell surface receptor that regulates microglial function and is involved in the pathophysiology of several neurodegenerative diseases. Its soluble form (sTREM2) results from shedding of the TREM2 ectodomain. The role of TREM2 in prion diseases, a group of rapidly progressive dementias remains to be elucidated. In the present study, we analysed the expression of TREM2 and its main sheddase ADAM10 in the brain of sporadic Creutzfeldt-Jakob disease (sCJD) patients and evaluated the role of CSF and plasma sTREM2 as a potential diagnostic marker of prion disease. Our data indicate that, compared to controls, TREM2 is increased in sCJD patient brains at the mRNA and protein levels in a regional and subtype dependent fashion, and expressed in a subpopulation of microglia. In contrast, ADAM10 is increased at the protein, but not the mRNA level, with a restricted neuronal expression. Elevated CSF sTREM2 is found in sCJD, genetic CJD with mutations E200K and V210I in the prion protein gene (PRNP), and iatrogenic CJD, as compared to healthy controls (HC) (AUC = 0.78-0.90) and neurological controls (AUC = 0.73-0.85), while CSF sTREM2 is unchanged in fatal familial insomnia. sTREM2 in the CSF of cases with Alzheimer's disease, and multiple sclerosis was not significantly altered in our series. CSF sTREM2 concentrations in sCJD are PRNP codon 129 and subtype-related, correlate with CSF 14-3-3 positivity, total-tau and YKL-40, and increase with disease progression. In plasma, sTREM2 is increased in sCJD compared with HC (AUC = 0.80), displaying positive correlations with plasma total-tau, neurofilament light, and YKL-40. We conclude that comparative study of TREM2 in brain and biological fluids of prion diseases reveals TREM2 to be altered in human prion diseases with a potential value in target engagement, patient stratification, and disease monitoring.
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http://dx.doi.org/10.1007/s00401-021-02296-1DOI Listing
April 2021

Dual Role of Lysophosphatidic Acid Receptor 2 (LPA) in Amyotrophic Lateral Sclerosis.

Front Cell Neurosci 2021 25;15:600872. Epub 2021 Mar 25.

Departament de Biologia Cellular, Fisiologia i Immunologia, Institut de Neurociències, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, Bellaterra, Spain.

Lysophosphatidic acid (LPA) is a pleiotropic extracellular lipid mediator with many physiological functions that signal through six known G protein-coupled receptors (LPA). In the central nervous system (CNS), LPA mediates a wide range of effects including neural progenitor cell physiology, neuronal cell death, axonal retraction, and inflammation. Since inflammation is a hallmark of most neurological conditions, we hypothesized that LPA could be involved in the physiopathology of amyotrophic lateral sclerosis (ALS). We found that LPA RNA was upregulated in post-mortem spinal cord samples of ALS patients and in the sciatic nerve and skeletal muscle of SOD1 mouse, the most widely used ALS mouse model. To assess the contribution of LPA to ALS, we generated a SOD1 mouse that was deficient in . This animal revealed that LPA signaling accelerates disease onset and neurological decline but, unexpectedly, extended the lifespan. To gain insights into the early harmful actions of LPA in ALS, we studied the effects of this receptor in the spinal cord, peripheral nerve, and skeletal muscle of ALS mice. We found that LPA gene deletion increased microglial activation but did not contribute to motoneuron death, astrogliosis, degeneration, and demyelination of motor axons. However, we observed that deficiency protected against muscle atrophy. Moreover, we also found the deletion of reduced the invasion of macrophages into the skeletal muscle of SOD1 mice, linking LPA signaling with muscle inflammation and atrophy in ALS. Overall, these results suggest for the first time that LPA contributes to ALS, and its genetic deletion results in protective actions at the early stages of the disease but shortens survival thereafter.
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http://dx.doi.org/10.3389/fncel.2021.600872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026865PMC
March 2021

Atypical astroglial pTDP-43 pathology in astroglial predominant tauopathy.

Neuropathol Appl Neurobiol 2021 Mar 17. Epub 2021 Mar 17.

Department of Pathology and Experimental Therapeutics, University of Barcelona, Bellvitge University Hospital-IDIBELL, CIBERNED, Hospitalet de Llobregat, Spain.

We observed atypical astrocytic pTDP-43 pathology in astroglial predominant tauopathy.
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http://dx.doi.org/10.1111/nan.12707DOI Listing
March 2021

Neuroimmune Response Mediated by Cytokines in Natural Scrapie after Chronic Dexamethasone Treatment.

Biomolecules 2021 02 2;11(2). Epub 2021 Feb 2.

Research Centre for Encephalopathies and Transmissible Emerging Diseases, Institute for Health Research Aragón (IIS), University of Zaragoza, C/Miguel Servet 155, 50013 Zaragoza, Spain.

The actual role of prion protein-induced glial activation and subsequent cytokine secretion during prion diseases is still incompletely understood. The overall aim of this study is to assess the effect of an anti-inflammatory treatment with dexamethasone on different cytokines released by neuroglial cells that are potentially related to neuroinflammation in natural scrapie. This study emphasizes the complex interactions existent among several pleiotropic neuromodulator peptides and provides a global approach to clarify neuroinflammatory processes in prion diseases. Additionally, an impairment of communication between microglial and astroglial populations mediated by cytokines, mainly IL-1, is suggested. The main novelty of this study is that it is the first one assessing in situ neuroinflammatory activity in relation to chronic anti-inflammatory therapy, gaining relevance because it is based on a natural model. The cytokine profile data would suggest the activation of some neurotoxicity-associated route. Consequently, targeting such a pathway might be a new approach to modify the damaging effects of neuroinflammation.
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http://dx.doi.org/10.3390/biom11020204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912810PMC
February 2021

TDP-43 Vasculopathy in the Spinal Cord in Sporadic Amyotrophic Lateral Sclerosis (sALS) and Frontal Cortex in sALS/FTLD-TDP.

J Neuropathol Exp Neurol 2021 Feb;80(3):229-239

Functional Unit of Amyotrophic Lateral Sclerosis (UFELA), Service of Neurology, Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain.

Sporadic amyotrophic lateral sclerosis (sALS) and FTLD-TDP are neurodegenerative diseases within the spectrum of TDP-43 proteinopathies. Since abnormal blood vessels and altered blood-brain barrier have been described in sALS, we wanted to know whether TDP-43 pathology also occurs in blood vessels in sALS/FTLD-TDP. TDP-43 deposits were identified in association with small blood vessels of the spinal cord in 7 of 14 cases of sALS and in small blood vessels of frontal cortex area 8 in 6 of 11 FTLD-TDP and sALS cases, one of them carrying a GRN mutation. This was achieved using single and double-labeling immunohistochemistry, and double-labeling immunofluorescence and confocal microscopy. In the sALS spinal cord, P-TDP43 Ser403-404 deposits were elongated and parallel to the lumen, whereas others were granular, seldom forming clusters. In the frontal cortex, the inclusions were granular, or elongated and parallel to the lumen, or forming small globules within or in the external surface of the blood vessel wall. Other deposits were localized in the perivascular space. The present findings are in line with previous observations of TDP-43 vasculopathy in a subset of FTLD-TDP cases and identify this pathology in the spinal cord and frontal cortex in a subset of cases within the sALS/FTLD-TDP spectrum.
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http://dx.doi.org/10.1093/jnen/nlaa162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899266PMC
February 2021

Lipid alterations in human frontal cortex in ALS-FTLD-TDP43 proteinopathy spectrum are partly related to peroxisome impairment.

Neuropathol Appl Neurobiol 2021 Jun 12;47(4):544-563. Epub 2021 Jan 12.

Neuropathology, Bellvitge University Hospital-Bellvitge Biomedical Research Institute (IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.

Aim: Peroxisomes play a key role in lipid metabolism, and peroxisome defects have been associated with neurodegenerative diseases such as X-adrenoleukodystrophy and Alzheimer's disease. This study aims to elucidate the contribution of peroxisomes in lipid alterations of area 8 of the frontal cortex in the spectrum of TDP43-proteinopathies. Cases of frontotemporal lobar degeneration-TDP43 (FTLD-TDP), manifested as sporadic (sFTLD-TDP) or linked to mutations in various genes including expansions of the non-coding region of C9ORF72 (c9FTLD), and of sporadic amyotrophic lateral sclerosis (sALS) as the most common TDP43 proteinopathies, were analysed.

Methods: We used transcriptomics and lipidomics methods to define the steady-state levels of gene expression and lipid profiles.

Results: Our results show alterations in gene expression of some components of peroxisomes and related lipid pathways in frontal cortex area 8 in sALS, sFTLD-TDP and c9FTLD. Additionally, we identify a lipidomic pattern associated with the ALS-FTLD-TDP43 proteinopathy spectrum, notably characterised by down-regulation of ether lipids and acylcarnitine among other lipid species, as well as alterations in the lipidome of each phenotype of TDP43 proteinopathy, which reveals commonalities and disease-dependent differences in lipid composition.

Conclusion: Globally, lipid alterations in the human frontal cortex of the ALS-FTLD-TDP43 proteinopathy spectrum, which involve cell membrane composition and signalling, vulnerability against cellular stress and possible glucose metabolism, are partly related to peroxisome impairment.
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http://dx.doi.org/10.1111/nan.12681DOI Listing
June 2021

Increased C-X-C Motif Chemokine Ligand 12 Levels in Cerebrospinal Fluid as a Candidate Biomarker in Sporadic Amyotrophic Lateral Sclerosis.

Int J Mol Sci 2020 Nov 17;21(22). Epub 2020 Nov 17.

Department of Pathology and Experimental Therapeutics, University of Barcelona, Feixa Llarga s/n, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.

Sporadic amyotrophic lateral sclerosis (sALS) is a fatal progressive neurodegenerative disease affecting upper and lower motor neurons. Biomarkers are useful to facilitate the diagnosis and/or prognosis of patients and to reveal possible mechanistic clues about the disease. This study aimed to identify and validate selected putative biomarkers in the cerebrospinal fluid (CSF) of sALS patients at early disease stages compared with age-matched controls and with other neurodegenerative diseases including Alzheimer disease (AD), spinal muscular atrophy type III (SMA), frontotemporal dementia behavioral variant (FTD), and multiple sclerosis (MS). SWATH acquisition on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for protein quantitation, and ELISA for validation, were used in CSF samples of sALS cases at early stages of the disease. Analysis of mRNA and protein expression was carried out in the anterior horn of the lumbar spinal cord in post-mortem tissue of sALS cases (terminal stage) and controls using RTq-PCR, and Western blotting, and immunohistochemistry, respectively. SWATH acquisition on liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed 51 differentially expressed proteins in the CSF in sALS. Receiver operating characteristic (ROC) curves showed CXCL12 to be the most valuable candidate biomarker. We validated the values of CXCL12 in CSF with ELISA in two different cohorts. Besides sALS, increased CXCL12 levels were found in MS but were not altered in AD, SMA, and FTD. Therefore, increased CXCL12 levels in the CSF can be useful in the diagnoses of MS and sALS in the context of the clinical settings. CXCL12 immunoreactivity was localized in motor neurons in control and sALS, and in a few glial cells in sALS at the terminal stage; CXCR4 was in a subset of oligodendroglial-like cells and axonal ballooning of motor neurons in sALS; and CXCR7 in motor neurons in control and sALS, and reactive astrocytes in the pyramidal tracts in terminal sALS. CXCL12/CXCR4/CXCR7 axis in the spinal cord probably plays a complex role in inflammation, oligodendroglial and astrocyte signaling, and neuronal and axonal preservation in sALS.
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http://dx.doi.org/10.3390/ijms21228680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698527PMC
November 2020

The Presence of Human Herpesvirus 6 in the Brain in Health and Disease.

Biomolecules 2020 11 6;10(11). Epub 2020 Nov 6.

Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain.

The human herpesvirus 6 (HHV-6) -A and -B are two dsDNA beta-herpesviruses infectingalmost the entire worldwide population. These viruses have been implicated in multipleneurological conditions in individuals of various ages and immunological status, includingencephalitis, epilepsy, and febrile seizures. HHV-6s have also been suggested as playing a role inthe etiology of neurodegenerative diseases such as multiple sclerosis and Alzheimer's disease. Theapparent robustness of these suggested associations is contingent on the accuracy of HHV-6detection in the nervous system. The effort of more than three decades of researching HHV-6 in thebrain has yielded numerous observations, albeit using variable technical approaches in terms oftissue preservation, detection techniques, sample sizes, brain regions, and comorbidities. In thisreview, we aimed to summarize current knowledge about the entry routes and direct presence ofHHV-6 in the brain parenchyma at the level of DNA, RNA, proteins, and specific cell types, inhealthy subjects and in those with neurological conditions. We also discuss recent findings relatedto the presence of HHV-6 in the brains of patients with Alzheimer's disease in light of availableevidence.
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http://dx.doi.org/10.3390/biom10111520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694807PMC
November 2020

Amyotrophic Lateral Sclerosis Is Accompanied by Protein Derangements in the Olfactory Bulb-Tract Axis.

Int J Mol Sci 2020 Nov 5;21(21). Epub 2020 Nov 5.

Clinical Neuroproteomics Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), Irunlarrea 3, 31008 Pamplona, Spain.

Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by progressive muscle paralysis due to the degeneration of upper and lower motor neurons. Recent studies point out an involvement of the non-motor axis during disease progression. Despite smell impairment being considered a potential non-motor finding in ALS, the pathobiochemistry at the olfactory level remains unknown. Here, we applied an olfactory quantitative proteotyping approach to analyze the magnitude of the olfactory bulb (OB) proteostatic imbalance in ALS subjects ( = 12) with respect to controls ( = 8). Around 3% of the quantified OB proteome was differentially expressed, pinpointing aberrant protein expression involved in vesicle-mediated transport, macroautophagy, axon development and gliogenesis in ALS subjects. The overproduction of olfactory marker protein () points out an imbalance in the olfactory signal transduction in ALS. Accompanying the specific overexpression of glial fibrillary acidic protein () and Bcl-xL in the olfactory tract (OT), a tangled disruption of signaling routes was evidenced across the OB-OT axis in ALS. In particular, the OB survival signaling dynamics clearly differ between ALS and frontotemporal lobar degeneration (FTLD), two faces of TDP-43 proteinopathy. To the best of our knowledge, this is the first report on high-throughput molecular characterization of the olfactory proteostasis in ALS.
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http://dx.doi.org/10.3390/ijms21218311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664257PMC
November 2020

Capacity for Seeding and Spreading of Argyrophilic Grain Disease in a Wild-Type Murine Model; Comparisons With Primary Age-Related Tauopathy.

Front Mol Neurosci 2020 24;13:101. Epub 2020 Jun 24.

CIBERNED (Network Centre of Biomedical Research of Neurodegenerative Diseases), Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain.

Argyrophilic grain disease (AGD) is a common 4R-tauopathy, causing or contributing to cognitive impairment in the elderly. AGD is characterized neuropathologically by pre-tangles in neurons, dendritic swellings called grains, threads, thorn-shaped astrocytes, and coiled bodies in oligodendrocytes in the limbic system. AGD has a characteristic pattern progressively involving the entorhinal cortex, amygdala, hippocampus, dentate gyrus, presubiculum, subiculum, hypothalamic nuclei, temporal cortex, and neocortex and brainstem, thus suggesting that argyrophilic grain pathology is a natural model of tau propagation. One series of WT mice was unilaterally inoculated in the hippocampus with sarkosyl-insoluble and sarkosyl-soluble fractions from "pure" AGD at the age of 3 or 7/12 months and killed 3 or 7 months later. Abnormal hyper-phosphorylated tau deposits were found in ipsilateral hippocampal neurons, grains (dots) in the hippocampus, and threads, dots and coiled bodies in the fimbria, as well as the ipsilateral and contralateral corpus callosum. The extension of lesions was wider in animals surviving 7 months compared with those surviving 3 months. Astrocytic inclusions were not observed at any time. Tau deposits were mainly composed of 4Rtau, but also 3Rtau. For comparative purposes, another series of WT mice was inoculated with sarkosyl-insoluble fractions from primary age-related tauopathy (PART), a pure neuronal neurofibrillary tangle 3Rtau + 4Rtau tauopathy involving the deep temporal cortex and limbic system. Abnormal hyper-phosphorylated tau deposits were found in neurons in the ipsilateral hippocampus, coiled bodies and threads in the fimbria, and the ipsilateral and contralateral corpus callosum, which extended with time along the anterior-posterior axis and distant regions such as hypothalamic nuclei and nuclei of the septum when comparing mice surviving 7 months with mice surviving 3 months. Astrocytic inclusions were not observed. Tau deposits were mainly composed of 4Rtau and 3Rtau. These results show the capacity for seeding and spreading of AGD tau and PART tau in the brain of WT mouse, and suggest that characteristics of host tau, in addition to those of inoculated tau, are key to identifying commonalities and differences between human tauopathies and corresponding murine models.
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http://dx.doi.org/10.3389/fnmol.2020.00101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326954PMC
June 2020

Cannabidiol-Enriched Extract Reduced the Cognitive Impairment but Not the Epileptic Seizures in a Lafora Disease Animal Model.

Cannabis Cannabinoid Res 2020 Jun 5;5(2):150-163. Epub 2020 Jun 5.

Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.

Lafora disease (LD) is a rare form of progressive infantile epilepsy in which rapid neurological deterioration occurs as the disease advances, leading the patients to a vegetative state and then death, usually within the first decade of disease onset. Based on the capacity of the endogenous cannabinoid system (ECS) to modulate several cellular processes commonly altered in many neurodegenerative processes, as well as the antiepileptic properties of certain natural cannabinoids, the aim of this study was to evaluate the role of the ECS in LD progression. We tested whether a natural cannabis extract highly enriched in cannabidiol (CBD) might be effective in curbing the pathological phenotype of malin knockout (KO) mice as an animal model of LD. Our results reveal for the first time that alterations in the ECS occur during the evolution of LD, mainly at the level of CB, CB, and G protein-coupled receptor 55 (GPR55) receptor expression, and that a CBD-enriched extract (CBDext) is able to reduce the cognitive impairment exhibited by malin KO mice. However, in contrast to what has previously been reported for other kinds of refractory epilepsy in childhood, the CBD-enriched extract does not reduce the severity of the epileptic seizures induced in this animal model of LD. In summary, this study reveals that the ECS might play a role in LD and that a CBD-enriched extract partially reduces the dementia-like phenotype, but not the increased vulnerability to epileptic seizures, exhibited by an animal model of such a life-threatening disease.
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http://dx.doi.org/10.1089/can.2019.0005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347043PMC
June 2020

Assessment of Glial Activation Response in the Progress of Natural Scrapie after Chronic Dexamethasone Treatment.

Int J Mol Sci 2020 May 2;21(9). Epub 2020 May 2.

Research Centre for Encephalopathies and Transmissible Emerging Diseases-Institute for Health Research Aragón (IIS), University of Zaragoza, C/Miguel Servet 155, 50013 Zaragoza, Spain.

Neuroinflammation has been correlated with the progress of neurodegeneration in many neuropathologies. Although glial cells have traditionally been considered to be protective, the concept of them as neurotoxic cells has recently emerged. Thus, a major unsolved question is the exact role of astroglia and microglia in neurodegenerative disorders. On the other hand, it is well known that glucocorticoids are the first choice to regulate inflammation and, consequently, neuroglial inflammatory activity. The objective of this study was to determine how chronic dexamethasone treatment influences the host immune response and to characterize the beneficial or detrimental role of glial cells. To date, this has not been examined using a natural neurodegenerative model of scrapie. With this aim, immunohistochemical expression of glial markers, prion protein accumulation, histopathological lesions and clinical evolution were compared with those in a control group. The results demonstrated how the complex interaction between glial populations failed to compensate for brain damage in natural conditions, emphasizing the need for using natural models. Additionally, the data showed that modulation of neuroinflammation by anti-inflammatory drugs might become a research focus as a potential therapeutic target for prion diseases, similar to that considered previously for other neurodegenerative disorders classified as prion-like diseases.
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http://dx.doi.org/10.3390/ijms21093231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247567PMC
May 2020

Motor neuron preservation and decrease of in vivo TDP-43 phosphorylation by protein CK-1δ kinase inhibitor treatment.

Sci Rep 2020 03 10;10(1):4449. Epub 2020 Mar 10.

Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain.

Pathogenesis of amyotrophic lateral sclerosis (ALS), a devastating disease where no treatment exists, involves the compartmentalization of the nuclear protein TDP-43 (TAR DNA-binding protein 43) in the cytoplasm which is promoted by its aberrant phosphorylation and others posttranslational modifications. Recently, it was reported that CK-1δ (protein casein kinase-1δ) is able to phosphorylate TDP-43. Here, the preclinical efficacy of a benzothiazole-based CK-1δ inhibitor IGS-2.7, both in a TDP-43 (A315T) transgenic mouse and in a human cell-based model of ALS, is shown. Treatment with IGS-2.7 produces a significant preservation of motor neurons in the anterior horn at lumbar level, a decrease in both astroglial and microglial reactivity in this area, and in TDP-43 phosphorylation in spinal cord samples. Furthermore, the recovery of TDP-43 homeostasis (phosphorylation and localization) in a human-based cell model from ALS patients after treatment with IGS-2.7 is also reported. Moreover, we have shown a trend to increase in CK-1δ mRNA in spinal cord and significantly in frontal cortex of sALS cases. All these data show for the first time the in vivo modulation of TDP-43 toxicity by CK-1δ inhibition with IGS-2.7, which may explain the benefits in the preservation of spinal motor neurons and point to the relevance of CK-1δ inhibitors in a future disease-modifying treatment for ALS.
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http://dx.doi.org/10.1038/s41598-020-61265-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064575PMC
March 2020

Familial globular glial tauopathy linked to MAPT mutations: molecular neuropathology and seeding capacity of a prototypical mixed neuronal and glial tauopathy.

Acta Neuropathol 2020 04 6;139(4):735-771. Epub 2020 Jan 6.

CIBERNED (Network Centre of Biomedical Research of Neurodegenerative Diseases), Ministry of Economy and Competitiveness, Institute of Health Carlos III, Madrid, Spain.

Globular glial tauopathy (GGT) is a progressive neurodegenerative disease involving the grey matter and white matter (WM) and characterized by neuronal deposition of hyper-phosphorylated, abnormally conformed, truncated, oligomeric 4Rtau in neurons and in glial cells forming typical globular astrocyte and oligodendrocyte inclusions (GAIs and GOIs, respectively) and coiled bodies. Present studies centre on four genetic GGT cases from two unrelated families bearing the P301T mutation in MAPT and one case of sporadic GGT (sGGT) and one case of GGT linked to MAPT K317M mutation, for comparative purposes. Clinical and neuropathological manifestations and biochemical profiles of phospho-tau are subjected to individual variations in patients carrying the same mutation, even in carriers of the same family, independently of the age of onset, gender, and duration of the disease. Immunohistochemistry, western blotting, transcriptomic, proteomics and phosphoproteomics, and intra-cerebral inoculation of brain homogenates to wild-type (WT) mice were the methods employed. In GGT cases linked to MAPT P301T mutation, astrocyte markers GFAP, ALDH1L1, YKL40 mRNA and protein, GJA1 mRNA, and AQ4 protein are significantly increased; glutamate transporter GLT1 (EAAT2) and glucose transporter (SLC2A1) decreased; mitochondrial pyruvate carrier 1 (MPC1) increased, and mitochondrial uncoupling protein 5 (UCP5) almost absent in GAIs in frontal cortex (FC). Expression of oligodendrocyte markers OLIG1 and OLIG2mRNA, and myelin-related genes MBP, PLP1, CNP, MAG, MAL, MOG, and MOBP are significantly decreased in WM; CNPase, PLP1, and MBP antibodies reveal reduction and disruption of myelinated fibres; and SMI31 antibodies mark axonal damage in the WM. Altered expression of AQ4, GLUC-t, and GLT-1 is also observed in sGGT and in GGT linked to MAPT K317M mutation. These alterations point to primary astrogliopathy and oligodendrogliopathy in GGT. In addition, GGT linked to MAPT P301T mutation proteotypes unveil a proteostatic imbalance due to widespread (phospho)proteomic dearrangement in the FC and WM, triggering a disruption of neuron projection morphogenesis and synaptic transmission. Identification of hyper-phosphorylation of variegated proteins calls into question the concept of phospho-tau-only alteration in the pathogenesis of GGT. Finally, unilateral inoculation of sarkosyl-insoluble fractions of GGT homogenates from GGT linked to MAPT P301T, sGGT, and GGT linked to MAPT K317M mutation in the hippocampus, corpus callosum, or caudate/putamen in wild-type mice produces seeding, and time- and region-dependent spreading of phosphorylated, non-oligomeric, and non-truncated 4Rtau and 3Rtau, without GAIs and GOIs but only of coiled bodies. These experiments prove that host tau strains are important in the modulation of cellular vulnerability and phenotypes of phospho-tau aggregates.
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http://dx.doi.org/10.1007/s00401-019-02122-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096369PMC
April 2020

Brain pyrimidine nucleotide synthesis and Alzheimer disease.

Aging (Albany NY) 2019 09 27;11(19):8433-8462. Epub 2019 Sep 27.

Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.

Many patients suffering late-onset Alzheimer disease show a deficit in respiratory complex IV activity. The pyrimidine biosynthesis pathway connects with the mitochondrial respiratory chain upstream from respiratory complex IV. We hypothesized that these patients would have decreased pyrimidine nucleotide levels. Then, different cell processes for which these compounds are essential, such as neuronal membrane generation and maintenance and synapses production, would be compromised. Using a cell model, we show that inhibiting oxidative phosphorylation function reduces neuronal differentiation. Linking these processes to pyrimidine nucleotides, uridine treatment recovers neuronal differentiation. To unmask the importance of these pathways in Alzheimer disease, we firstly confirm the existence of the pyrimidine biosynthesis pathway in adult human brain. Then, we report altered mRNA levels for genes from both pyrimidine biosynthesis and pyrimidine salvage pathways in brain from patients with Alzheimer disease. Thus, uridine supplementation might be used as a therapy for those Alzheimer disease patients with low respiratory complex IV activity.
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http://dx.doi.org/10.18632/aging.102328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814620PMC
September 2019

Relevance of host tau in tau seeding and spreading in tauopathies.

Brain Pathol 2020 03 27;30(2):298-318. Epub 2019 Aug 27.

CIBERNED (Network Centre of Biomedical Research of Neurodegenerative Diseases), Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain.

Human tau seeding and spreading occur following intracerebral inoculation of brain homogenates obtained from tauopathies in transgenic mice expressing natural or mutant tau, and in wild-type (WT) mice. The present study was geared to learning about the patterns of tau seeding, the cells involved and the characteristics of tau following intracerebral inoculation of homogenates from primary age-related tauopathy (PART: neuronal 4Rtau and 3Rtau), aging-related tau astrogliopathy (ARTAG: astrocytic 4Rtau) and globular glial tauopathy (GGT: 4Rtau with neuronal deposits and specific tau inclusions in astrocytes and oligodendrocytes). For this purpose, young and adult WT mice were inoculated unilaterally in the hippocampus or in the lateral corpus callosum with sarkosyl-insoluble fractions from PART, ARTAG and GGT cases, and were killed at variable periods of three to seven months. Brains were processed for immunohistochemistry in paraffin sections. Tau seeding occurred in the ipsilateral hippocampus and corpus callosum and spread to the septal nuclei, periventricular hypothalamus and contralateral corpus callosum, respectively. Tau deposits were mainly found in neurons, oligodendrocytes and threads; the deposits were diffuse or granular, composed of phosphorylated tau, tau with abnormal conformation and 3Rtau and 4Rtau independently of the type of tauopathy. Truncated tau at the aspartic acid 421 and ubiquitination were absent. Tau deposits had the characteristics of pre-tangles. A percentage of intracellular tau deposits co-localized with active (phosphorylated) tau kinases p38 and ERK 1/2. Present study shows that seeding and spreading of human tau into the brain of WT mice involves neurons and glial cells, mainly oligodendrocytes, thereby supporting the idea of a primary role of oligodendrogliopathy, together with neuronopathy, in the progression of tauopathies. In addition, it suggests that human tau inoculation modifies murine tau metabolism with the production and deposition of 3Rtau and 4Rtau, and by activation of specific tau kinases in affected cells.
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http://dx.doi.org/10.1111/bpa.12778DOI Listing
March 2020

Involvement of Oligodendrocytes in Tau Seeding and Spreading in Tauopathies.

Front Aging Neurosci 2019 28;11:112. Epub 2019 May 28.

CIBERNED (Network Centre of Biomedical Research of Neurodegenerative Diseases), Institute of Health Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain.

Human tau seeding and spreading occur following intracerebral inoculation into different gray matter regions of brain homogenates obtained from tauopathies in transgenic mice expressing wild or mutant tau, and in wild-type (WT) mice. However, little is known about tau propagation following inoculation in the white matter. The present study is geared to learning about the patterns of tau seeding and cells involved following unilateral inoculation in the corpus callosum of homogenates from sporadic Alzheimer's disease (AD), primary age-related tauopathy (PART: neuronal 4Rtau and 3Rtau), pure aging-related tau astrogliopathy (ARTAG: astroglial 4Rtau with thorn-shaped astrocytes TSAs), globular glial tauopathy (GGT: 4Rtau with neuronal tau and specific tau inclusions in astrocytes and oligodendrocytes, GAIs and GOIs, respectively), progressive supranuclear palsy (PSP: 4Rtau with neuronal inclusions, tufted astrocytes and coiled bodies), Pick's disease (PiD: 3Rtau with characteristic Pick bodies in neurons and tau containing fibrillar astrocytes), and frontotemporal lobar degeneration linked to P301L mutation (FTLD-P301L: 4Rtau familial tauopathy). Adult WT mice were inoculated unilaterally in the lateral corpus callosum with sarkosyl-insoluble fractions or with sarkosyl-soluble fractions from the mentioned tauopathies; mice were killed from 4 to 7 months after inoculation. Brains were fixed in paraformaldehyde, embedded in paraffin and processed for immunohistochemistry. Tau seeding occurred in the ipsilateral corpus callosum and was also detected in the contralateral corpus callosum. Phospho-tau deposits were found in oligodendrocytes similar to coiled bodies and in threads. Moreover, tau deposits co-localized with active (phosphorylated) tau kinases p38 and ERK 1/2, suggesting active tau phosphorylation of murine tau. TSAs, GAIs, GOIs, tufted astrocytes, and tau-containing fibrillar astrocytes were not seen in any case. Tau deposits were often associated with slight myelin disruption and the presence of small PLP1-immunoreactive globules and dots in the ipsilateral corpus callosum 6 months after inoculation of sarkosyl-insoluble fractions from every tauopathy. Seeding and spreading of human tau in the corpus callosum of WT mice occurs in oligodendrocytes, thereby supporting the idea of a role of oligodendrogliopathy in tau seeding and spreading in the white matter in tauopathies. Slight differences in the predominance of threads or oligodendroglial deposits suggest disease differences in the capacity of tau seeding and spreading among tauopathies.
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http://dx.doi.org/10.3389/fnagi.2019.00112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546889PMC
May 2019

Altered Dynein Axonemal Assembly Factor 1 Expression in C-Boutons in Bulbar and Spinal Cord Motor-Neurons in Sporadic Amyotrophic Lateral Sclerosis.

J Neuropathol Exp Neurol 2019 05;78(5):416-425

Department of Pathology and Experimental Therapeutics, University of Barcelona, Spain.

Dyneins are major components of microtubules. Dynein assembly is modulated by a heterogeneous group of dynein axonemal assembly factors (DNAAFs). The present study analyzes dynein axonemal assembly factor 1 (DNAAF1) and leucine-rich repeat-containing protein 50 (LRRC50), the corresponding encoded protein, in lower motor neurons in spinal cord of sALS postmortem samples and hSOD1-G93A transgenic mice compared with controls. DNAAF1 mRNA is significantly reduced in the anterior horn in sALS, and LRRC50 immunoreactivity is significantly reduced in C-boutons of the remaining motor neurons of the anterior horn, dorsal nucleus of the vagus nerve, and hypoglossal nuclei at terminal stages of ALS. LRRC50 immunoreactivity has a perinuclear distribution in motor neurons in sALS thus suggesting a disorder of transport. The number of LRRC50-/S1R-immunoreactive structures is also significantly decreased in hSOD1-G93A transgenic mice at the age of 90 days (preclinical stages), and the number of motor neurons with LRRC50-immunoreactive structures is significantly reduced in animals aged 150 days (clinical stages). These observations suggest cholinergic denervation of motor neurons as a pathogenic factor in motor neuron disease. LRRC50 protein levels were not detected in human CSF.
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http://dx.doi.org/10.1093/jnen/nlz019DOI Listing
May 2019

Wnt Signaling Alterations in the Human Spinal Cord of Amyotrophic Lateral Sclerosis Cases: Spotlight on Fz2 and Wnt5a.

Mol Neurobiol 2019 Oct 28;56(10):6777-6791. Epub 2019 Mar 28.

Molecular Neurology Group, Hospital Nacional de Parapléjicos (HNP), Finca la Peraleda s/n, 45071, Toledo, Spain.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with no cure, and elucidation of the mechanisms mediating neuronal death in this neuropathology is crucial to develop effective treatments. It has recently been demonstrated in animal models that the Wnt family of proteins is involved in this neuropathology, although its potential involvement in case of humans is almost unknown. We analyzed the expression of Wnt signaling components in healthy and ALS human spinal cords by quantitative RT-PCR, and we found that most Wnt ligands, modulators, receptors, and co-receptors were expressed in healthy controls. Moreover, we observed clear alterations in the mRNA expression of different components of this family of proteins in human spinal cord tissue from ALS cases. Specifically, we detected a significant increase in the mRNA levels of Wnt3, Wnt4, Fz2, and Fz8, together with several non-significant increases in the mRNA expression of other genes such as Wnt2b, Wnt5a, Fz3, Lrp5, and sFRP3. Based on these observations and on previous reports of studies performed in animal models, we evaluated with immunohistochemistry the protein expression patterns of Fz2 and Fz5 receptors and their main ligand Wnt5a in control samples and ALS cases. No substantial changes were observed in Fz5 protein expression pattern in ALS samples. However, we detected an increase in the amount of Fz2+ astrocytes in the borderline between gray and white matter at the ventral horn in ALS samples. Finally, Wnt5a expression was observed in neurons and astrocytes in both control and ALS samples, although Wnt5a immunolabeling in astroglial cells was significantly increased in ALS spinal cords in the same region where changes in Fz2 were observed. Altogether, these observations strongly suggest that the Wnt family of proteins, and more specifically Fz2 and Wnt5a, might be involved in human ALS pathology.
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http://dx.doi.org/10.1007/s12035-019-1547-9DOI Listing
October 2019

Combined Transcriptomics and Proteomics in Frontal Cortex Area 8 in Frontotemporal Lobar Degeneration Linked to C9ORF72 Expansion.

J Alzheimers Dis 2019 ;68(3):1287-1307

Neuropathology, Pathologic Anatomy Service, Bellvitge University Hospital - Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Spain.

Background: Frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP) may appear as sporadic (sFTLD-TDP) or linked to mutations in various genes including expansions of the non-coding region of C9ORF72 (c9FTLD).

Objective: Analysis of differential mRNA and protein expression in the frontal cortex in c9FLTD and evaluation with previous observations in frontal cortex in sFTLD-TDP and amyotrophic lateral sclerosis with TDP-43 inclusions.

Methods: Microarray hybridization and mass spectrometry-based quantitative proteomics followed by RT-qPCR, gel electrophoresis, and western blotting in frontal cortex area 8 in 19 c9FTLD cases and 14 age- and gender-matched controls.

Results: Microarray hybridization distinguish altered gene transcription related to DNA recombination, RNA splicing regulation, RNA polymerase transcription, myelin synthesis, calcium regulation, and ubiquitin-proteasome system in c9FTLD; proteomics performed in the same tissue samples pinpoints abnormal protein expression involving apoptosis, inflammation, metabolism of amino acids, metabolism of carbohydrates, metabolism of membrane lipid derivatives, microtubule dynamics, morphology of mitochondria, neuritogenesis, neurotransmission, phagocytosis, receptor-mediated endocytosis, synthesis of reactive oxygen species, and calcium signaling in c9FTLD.

Conclusion: Transcriptomics and proteomics, as well as bioinformatics processing of derived data, reveal similarly altered pathways in the frontal cortex in c9FTLD, but different RNAs and proteins are identified by these methods. Combined non-targeted '-omics' is a valuable approach to deciphering altered molecular pathways in FTLD provided that observations are approached with caution when assessing human postmortem brain samples.
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http://dx.doi.org/10.3233/JAD-181123DOI Listing
August 2020

PPARγ agonist-loaded PLGA-PEG nanocarriers as a potential treatment for Alzheimer's disease: in vitro and in vivo studies.

Int J Nanomedicine 2018 20;13:5577-5590. Epub 2018 Sep 20.

School of Life, Health and Chemical Sciences, Faculty of Science, The Open University, Walton Hall, Milton Keynes, UK,

Objective: The first aim of this study was to develop a nanocarrier that could transport the peroxisome proliferator-activated receptor agonist, pioglitazone (PGZ) across brain endothelium and examine the mechanism of nanoparticle transcytosis. The second aim was to determine whether these nanocarriers could successfully treat a mouse model of Alzheimer's disease (AD).

Methods: PGZ-loaded nanoparticles (PGZ-NPs) were synthesized by the solvent displacement technique, following a factorial design using poly (lactic-co-glycolic acid) polyethylene glycol (PLGA-PEG). The transport of the carriers was assessed in vitro, using a human brain endothelial cell line, cytotoxicity assays, fluorescence-tagged nanocarriers, fluorescence-activated cell sorting, confocal and transmission electron microscopy. The effectiveness of the treatment was assessed in APP/PS1 mice in a behavioral assay and by measuring the cortical deposition of β-amyloid.

Results: Incorporation of PGZ into the carriers promoted a 50x greater uptake into brain endothelium compared with the free drug and the carriers showed a delayed release profile of PGZ in vitro. In the doses used, the nanocarriers were not toxic for the endothelial cells, nor did they alter the permeability of the blood-brain barrier model. Electron microscopy indicated that the nanocarriers were transported from the apical to the basal surface of the endothelium by vesicular transcytosis. An efficacy test carried out in APP/PS1 transgenic mice showed a reduction of memory deficit in mice chronically treated with PGZ-NPs. Deposition of β-amyloid in the cerebral cortex, measured by immunohistochemistry and image analysis, was correspondingly reduced.

Conclusion: PLGA-PEG nanocarriers cross brain endothelium by transcytosis and can be loaded with a pharmaceutical agent to effectively treat a mouse model of AD.
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http://dx.doi.org/10.2147/IJN.S171490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6154713PMC
November 2018

YKL40 in sporadic amyotrophic lateral sclerosis: cerebrospinal fluid levels as a prognosis marker of disease progression.

Aging (Albany NY) 2018 09;10(9):2367-2382

Department of Pathology and Experimental Therapeutics, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.

Amyotrophic lateral sclerosis (ALS) has variable clinical course and fatal outcome. Since inflammation plays a role in the pathogenesis of ALS, chitinase-3-like protein 1 or YKL40 has been assessed as putative biomarker of disease progression. YKL40 mRNA levels are increased in anterior horn of the spinal cord (0.004) in sporadic ALS (sALS) cases when compared with age-matched controls. These correlate with increased mRNA expression of microglial markers and in the spinal cord in sALS (0.044 and 0.000, respectively). YKL40 mRNA and protein expression had a tendency to increase in post-mortem frontal cortex area 8 (0.06 and 0.08, respectively). Yet YKL40 immunoreactivity is restricted to a subpopulation of astrocytes in these regions. YKL40 protein levels, as revealed by enzyme-linked immunosorbent assay (ELISA), are significantly increased in the CSF in sALS (n=86) compared with age-matched controls (n=21) (=0.045). Higher levels are found in patients with fast progression when compared with patients with slow and normal progression (=0.008 and =0.004, respectively), and correlates with ALS-FRS-R slope (=0.000). Additionally, increased protein levels of neurofilament light chain (NF-L) are also found in sALS (=0.000); highest values are found in patients with fast progression when compared with cases with slow and normal progression (=0.005 and =0.000, respectively), and also correlate with ALS-FRS-R slope (=0.000). Pearson's correlation test linked positively the increased levels of YKL40 with increased NF-L levels (=0.013). These data point to YKL40 and NF-L protein levels in the CSF as a good biomarker combination of disease progression in sALS.
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http://dx.doi.org/10.18632/aging.101551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6188478PMC
September 2018

Genetic deletion of CB cannabinoid receptors exacerbates the Alzheimer-like symptoms in a transgenic animal model.

Biochem Pharmacol 2018 11 7;157:210-216. Epub 2018 Aug 7.

Department of Pathology and Experimental Therapeutics, University of Barcelona-IDIBELL, L'Hospitalet de Llobregat, Spain; CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Spain.

Activating CB cannabinoid receptor has been demonstrated to produce certain therapeutic effects in animal models of Alzheimer's disease (AD). In this study, we evaluated the specific contribution of CB receptor to the progression of AD-like pathology in double transgenic APP/PS1 mice. A new mouse strain was generated by crossing APP/PS1 transgenic mice with CB knockout mice. Genetic deletion of CB drastically reduced the survival of APP/PS1 mice. In spite that CB mutant mice bearing the APP/PS1 transgene developed normally, they suddenly died within the first two months of life likely due to spontaneous seizures. This increased mortality could be related to an imbalance in the excitatory/inhibitory transmission in the hippocampus as suggested by the reduced density of inhibitory parvalbumin positive neurons observed in APP/PS1 mice lacking CB receptor at 7 weeks of age. We also evaluated the AD-like phenotype of APP/PS1 mice heterozygous for the CB deletion at 3 and 6 months of age. The memory impairment associated to APP/PS1 transgene was accelerated in these mice. Neither the soluble levels of Aβ or the density of Aβ plaques were modified in APP/PS1 mice heterozygous for CB deletion at any age. However, the reduction in CB receptor expression decreased the levels of PSD-95 protein in APP/PS1 mice, suggesting a synaptic dysfunction in these animals that could account for the acceleration of the memory impairment observed. In summary, our results suggest a crucial role for CB receptor in the progression of AD-related pathological events.
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http://dx.doi.org/10.1016/j.bcp.2018.08.007DOI Listing
November 2018

Altered gene transcription linked to astrocytes and oligodendrocytes in frontal cortex in Creutzfeldt-Jakob disease.

Prion 2018 27;12(3-4):216-225. Epub 2018 Jul 27.

a Department of Pathology and Experimental Therapeutics , University of Barcelona.

Targeted expression of genes coding for proteins specific to astrocytes, oligodendrocytes and myelin was performed in frontal cortex area 8 of Creutzfeldt-Jakob disease methionine/methionine and valine/valine (CJD MM1 and VV2, respectively) compared with controls. GFAP (glial fibrillary acidic protein) mRNA was up-regulated whereas SLC1A2 (solute carrier family 1 member 2, coding for glutamate transporter 1: GLT1), AQ4 (aquaporin 4), MPC1 (mitochondrial pyruvate carrier 1) and UCP5 (mitochondrial uncoupled protein 5) mRNAs were significantly down-regulated in CJD MM1 and CJD VV2, and GJA1 (connexin 43) in CJD VV2. OLIG1 and OLIG2 (oligodendocyte transcription factor 1 and 2, respectively), SOX10 (SRY-Box10) and oligodendroglial precursor cell (OPC) marker NG2 (neuronal/glial antigen) 2 were preserved, but GALC (coding for galactosylceramidase), SLC2A1 (solute carrier family 2 member 1: glucose transporter member 1: GLUT1) and MCT1 (monocarboxylic acid transporter 1) mRNA expression levels were significantly reduced in CJD MM1 and CJD VV2. Expression levels of most genes linked to myelin were not altered in the cerebral cortex in CJD. Immunohistochemistry to selected proteins disclosed individual variations but GFAP, Olig-2, AQ4 and GLUT1 correlated with mRNA levels, whereas GLT1 was subjected to individual variations. However, MPC1, UCP5 and MCT1 decrease was more closely related to the respective reduced neuronal immunostaining. These observations support the idea that molecular deficits linked to energy metabolism and solute transport in astrocytes and oligodendrocytes, in addition to neurons, are relevant in the pathogenesis of cortical lesions in CJD.
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http://dx.doi.org/10.1080/19336896.2018.1500076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277179PMC
February 2019

Altered Regulation of KIAA0566, and Katanin Signaling Expression in the Locus Coeruleus With Neurofibrillary Tangle Pathology.

Front Cell Neurosci 2018 17;12:131. Epub 2018 May 17.

Neuropathology, Pathologic Anatomy Service, Bellvitge Biomedical Research Institute, Hospitalet de Llobregat, Bellvitge University Hospital, Barcelona, Spain.

The locus coeruleus (LC), which contains the largest group of noradrenergic neurons in the central nervous system innervating the telencephalon, is an early and constantly vulnerable region to neurofibrillary tangle (NFT) pathology in aging and Alzheimer's disease (AD). The present study using whole genome bisulfite sequencing and Infinium Human Methylation 450 BeadChip was designed to learn about DNA methylation profiles in LC with age and NFT pathology. This method identified decreased DNA methylation of Katanin-Interacting Protein gene ( linked to age and presence of NFT pathology. mRNA expression demonstrated with RT-qPCR significantly decreased in cases with NFT pathology. Importantly, KIAA0566 immunoreactivity was significantly decreased only in LC neurons with NFTs, but not in neurons without tau pathology when compared with neurons of middle-aged individuals. These changes were accompanied by a similar pattern of selective p80-katanin reduced protein expression in neurons with NFTs. In contrast, p60-katanin subunit expression levels in the neuropil were similar in MA cases and cases with NFT pathology. Since katanin is a major microtubule-severing protein and KIAA0566 binds and interacts with katanin, de-regulation of the katanin-signaling pathway may have implications in the regulation of microtubule homeostasis in LC neurons with NFTs, thereby potentially interfering with maintenance of the cytoskeleton and transport.
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http://dx.doi.org/10.3389/fncel.2018.00131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966574PMC
May 2018

Gene Expression Profile in Frontal Cortex in Sporadic Frontotemporal Lobar Degeneration-TDP.

J Neuropathol Exp Neurol 2018 07;77(7):608-627

Neuropathology, Pathologic Anatomy Service, Bellvitge University Hospital, IDIBELL, Hospitalet de Llobregat, Spain.

Molecular alterations compromising key metabolic pathways are poorly understood in sporadic frontotemporal lobar degeneration with TDP-43 pathology (sFTLD-TDP). Whole-transcriptome array, RT-qPCR validation, gel electrophoresis, and Western blotting, and mitochondrial electron transport chain (ETC) activity were comparatively examined in frontal cortex (area 8) of 16 sFTLD-TDP cases and 14 controls. Assessment of 111 genes by RT-qPCR showed deregulation of 81 genes linked to neurotransmission and synapses, neuronal architecture, cytoskeleton of axons and dendrites, vesicle trafficking, purines, mitochondria, and energy metabolism in sFTLD-TDP. Western blotting studies disclosed downregulation of several mitochondrial subunits encoded by genomic DNA and MT-CO1 encoded by the mitochondrial DNA. Mitochondrial ETC activity of complexes I, IV, and V was decreased in sFTLD-TDP. These findings provide robust information about downregulation of genes involved in vital biochemical pathways and in synaptic neurotransmission which may help to increase understanding about the biochemical substrates of clinical manifestations in sFTLD-TDP.
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http://dx.doi.org/10.1093/jnen/nly037DOI Listing
July 2018

Inflammatory Gene Expression in Whole Peripheral Blood at Early Stages of Sporadic Amyotrophic Lateral Sclerosis.

Front Neurol 2017 13;8:546. Epub 2017 Oct 13.

Neuropathology, Pathologic Anatomy Service, Bellvitge University Hospital, IDIBELL, Hospitalet de Llobregat, Spain.

Objective: Characterization of altered expression of selected transcripts linked to inflammation in the peripheral blood of sporadic amyotrophic lateral sclerosis (sALS) patients at early stage of disease to increase knowledge about peripheral inflammatory response in sALS.

Methods: RNA expression levels of 45 genes were assessed by RT-qPCR in 22 sALS cases in parallel with 13 age-matched controls. Clinical and serum parameters were assessed at the same time.

Results: Upregulation of genes coding for factors involved in leukocyte extravasation (, and ) and extracellular matrix remodeling ( and ), as well as downregulation of certain chemokines ( and ), anti-inflammatory cytokines (, and ), pro-inflammatory cytokines (), and T-cell regulators ( and ) was found in sALS cases independently of gender, clinical symptoms at onset (spinal, respiratory, or bulbar), progression, peripheral leukocyte number, and integrity of RNA. levels positively correlated with age, whereas , and negatively correlated with age in sALS but not in controls. Relatively higher expression levels correlate with higher creatinine kinase protein levels in plasma.

Conclusion: Present findings show early inflammatory responses characterized by upregulation of factors enabling extravasation of leukocytes and extracellular matrix remodeling in blood in sALS cases, in addition to increased levels paralleling skeletal muscle damage.
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http://dx.doi.org/10.3389/fneur.2017.00546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645505PMC
October 2017