18 results on '"Mar Hernandez-Guillamon"'
Search Results
2. The presence of circulating human apolipoprotein J reduces the occurrence of cerebral microbleeds in a transgenic mouse model with cerebral amyloid angiopathy
- Author
-
Anna Bonaterra-Pastra, Montse Solé, Silvia Lope-Piedrafita, Maria Lucas-Parra, Laura Castellote, Paula Marazuela, Olalla Pancorbo, David Rodríguez-Luna, and Mar Hernández-Guillamon
- Subjects
Amyloid-β ,Apolipoprotein J ,Cerebral amyloid Angiopathy ,Cerebral microbleeds ,MMP-12 ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Cerebral amyloid angiopathy (CAA) is characterized by amyloid-β (Aβ) deposition in cerebral vessels, leading to lobar cerebral microbleeds (CMB) and intracerebral hemorrhages (ICH). Apolipoprotein J (ApoJ) is a multifunctional chaperone related to Aβ aggregation and clearance. Our study investigated the vascular impact of chronic recombinant human Apolipoprotein J (rhApoJ) treatment in a transgenic mouse model of β-amyloidosis with prominent CAA. Methods Twenty-month-old APP23 C57BL/6 mice received 25 doses of rhApoJ (1 mg/kg) (n = 9) or saline (n = 8) intraperitoneally for 13 weeks, while Wild-type (WT) mice received saline (n = 13). Postmortem brains underwent T2*-weighted magnetic resonance imaging (MRI) to detect hemorrhagic lesions. Aβ levels and distribution, cerebral fibrinogen leakage, brain smooth muscle actin (sma), and plasma matrix metalloproteinases and inflammatory markers were analyzed after treatments. Additionally, plasma samples from 22 patients with lobar ICH were examined to determine the clinical relevance of the preclinical findings. Results rhApoJ-treated APP23 presented fewer cortical CMBs (50–300 μm diameter) (p = 0.012) and cortical larger hemorrhages (> 300 μm) (p = 0.002) than saline-treated mice, independently of Aβ brain levels. MRI-detected hemorrhagic lesions correlated with fibrinogen cerebral extravasation (p = 0.011). Additionally, rhApoJ-treated mice presented higher number of sma-positive vessels than saline-treated mice (p = 0.038). In rhApoJ-treated mice, human ApoJ was detected in plasma and in occasional leptomeningeal vessels, but not in the parenchyma, suggesting that its mechanism of action operates through the periphery. The administration of rhApoJ induced an increase in plasma Groα (p = 0.035) and MIP-1α (p = 0.035) levels, while lower MMP-12 (p = 0.046) levels, compared to the saline-treated group. In acute lobar ICH patients, MMP-12 plasma levels correlated with larger hemorrhage volume (p = 0.040) and irregular ICH shape (p = 0.036). Conclusions Chronic rhApoJ treatment in aged APP23 mice ameliorated CAA-related neurovascular damage by reducing the occurrence of CMB. We propose that rhApoJ may prevent blood-brain barrier (BBB) leakage and CMB appearance partly through circulating MMP-12 modulation.
- Published
- 2024
- Full Text
- View/download PDF
3. The Boston criteria version 2.0 for cerebral amyloid angiopathy: a multicentre, retrospective, MRI-neuropathology diagnostic accuracy study
- Author
-
Andreas Charidimou, Gregoire Boulouis, Matthew P Frosch, Jean-Claude Baron, Marco Pasi, Jean Francois Albucher, Gargi Banerjee, Carmen Barbato, Fabrice Bonneville, Sebastian Brandner, Lionel Calviere, François Caparros, Barbara Casolla, Charlotte Cordonnier, Marie-Bernadette Delisle, Vincent Deramecourt, Martin Dichgans, Elif Gokcal, Jochen Herms, Mar Hernandez-Guillamon, Hans Rolf Jäger, Zane Jaunmuktane, Jennifer Linn, Sergi Martinez-Ramirez, Elena Martínez-Sáez, Christian Mawrin, Joan Montaner, Solene Moulin, Jean-Marc Olivot, Fabrizio Piazza, Laurent Puy, Nicolas Raposo, Mark A Rodrigues, Sigrun Roeber, Jose Rafael Romero, Neshika Samarasekera, Julie A Schneider, Stefanie Schreiber, Frank Schreiber, Corentin Schwall, Colin Smith, Levente Szalardy, Pascale Varlet, Alain Viguier, Joanna M Wardlaw, Andrew Warren, Frank A Wollenweber, Marialuisa Zedde, Mark A van Buchem, M Edip Gurol, Anand Viswanathan, Rustam Al-Shahi Salman, Eric E Smith, David J Werring, Steven M Greenberg, Charidimou, A, Boulouis, G, Frosch, M, Baron, J, Pasi, M, Albucher, J, Banerjee, G, Barbato, C, Bonneville, F, Brandner, S, Calviere, L, Caparros, F, Casolla, B, Cordonnier, C, Delisle, M, Deramecourt, V, Dichgans, M, Gokcal, E, Herms, J, Hernandez-Guillamon, M, Jäger, H, Jaunmuktane, Z, Linn, J, Martinez-Ramirez, S, Martínez-Sáez, E, Mawrin, C, Montaner, J, Moulin, S, Olivot, J, Piazza, F, Puy, L, Raposo, N, Rodrigues, M, Roeber, S, Romero, J, Samarasekera, N, Schneider, J, Schreiber, S, Schreiber, F, Schwall, C, Smith, C, Szalardy, L, Varlet, P, Viguier, A, Wardlaw, J, Warren, A, Wollenweber, F, Zedde, M, van Buchem, M, Gurol, M, Viswanathan, A, Al-Shahi Salman, R, Smith, E, Werring, D, and Greenberg, S
- Subjects
diagnoisi ,Amyloid beta-Peptides ,pathology [Cerebral Hemorrhage] ,Middle Aged ,MED/46 - SCIENZE TECNICHE DI MEDICINA DI LABORATORIO ,Magnetic Resonance Imaging ,diagnostic imaging [Cerebral Amyloid Angiopathy] ,Cerebral Amyloid Angiopathy ,methods [Magnetic Resonance Imaging] ,biomarker ,Humans ,Neurology (clinical) ,ddc:610 ,Neuropathology ,MRI ,Aged ,Cerebral Hemorrhage ,Retrospective Studies - Abstract
BACKGROUND: Cerebral amyloid angiopathy (CAA) is an age-related small vessel disease, characterised pathologically by progressive deposition of amyloid β in the cerebrovascular wall. The Boston criteria are used worldwide for the in-vivo diagnosis of CAA but have not been updated since 2010, before the emergence of additional MRI markers. We report an international collaborative study aiming to update and externally validate the Boston diagnostic criteria across the full spectrum of clinical CAA presentations.METHODS: In this multicentre, hospital-based, retrospective, MRI and neuropathology diagnostic accuracy study, we did a retrospective analysis of clinical, radiological, and histopathological data available to sites participating in the International CAA Association to formulate updated Boston criteria and establish their diagnostic accuracy across different populations and clinical presentations. Ten North American and European academic medical centres identified patients aged 50 years and older with potential CAA-related clinical presentations (ie, spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes), available brain MRI, and histopathological assessment for CAA diagnosis. MRI scans were centrally rated at Massachusetts General Hospital (Boston, MA, USA) for haemorrhagic and non-haemorrhagic CAA markers, and brain tissue samples were rated by neuropathologists at the contributing sites. We derived the Boston criteria version 2.0 (v2.0) by selecting MRI features to optimise diagnostic specificity and sensitivity in a prespecified derivation cohort (Boston cases 1994-2012, n=159), then externally validated the criteria in a prespecified temporal validation cohort (Boston cases 2012-18, n=59) and a geographical validation cohort (non-Boston cases 2004-18; n=123), comparing accuracy of the new criteria to the currently used modified Boston criteria with histopathological assessment of CAA as the diagnostic standard. We also assessed performance of the v2.0 criteria in patients across all cohorts who had the diagnostic gold standard of brain autopsy.FINDINGS: The study protocol was finalised on Jan 15, 2017, patient identification was completed on Dec 31, 2018, and imaging analyses were completed on Sept 30, 2019. Of 401 potentially eligible patients presenting to Massachusetts General Hospital, 218 were eligible to be included in the analysis; of 160 patient datasets from other centres, 123 were included. Using the derivation cohort, we derived provisional criteria for probable CAA requiring the presence of at least two strictly lobar haemorrhagic lesions (ie, intracerebral haemorrhages, cerebral microbleeds, or foci of cortical superficial siderosis) or at least one strictly lobar haemorrhagic lesion and at least one white matter characteristic (ie, severe visible perivascular spaces in centrum semiovale or white matter hyperintensities in a multispot pattern). The sensitivity and specificity of these criteria were 74·8% (95% CI 65·4-82·7) and 84·6% (71·9-93·1) in the derivation cohort, 92·5% (79·6-98·4) and 89·5% (66·9-98·7) in the temporal validation cohort, 80·2% (70·8-87·6) and 81·5% (61·9-93·7) in the geographical validation cohort, and 74·5% (65·4-82·4) and 95·0% (83·1-99·4) in all patients who had autopsy as the diagnostic standard. The area under the receiver operating characteristic curve (AUC) was 0·797 (0·732-0·861) in the derivation cohort, 0·910 (0·828-0·992) in the temporal validation cohort, 0·808 (0·724-0·893) in the geographical validation cohort, and 0·848 (0·794-0·901) in patients who had autopsy as the diagnostic standard. The v2.0 Boston criteria for probable CAA had superior accuracy to the current Boston criteria (sensitivity 64·5% [54·9-73·4]; specificity 95·0% [83·1-99·4]; AUC 0·798 [0·741-0854]; p=0·0005 for comparison of AUC) across all individuals who had autopsy as the diagnostic standard.INTERPRETATION: The Boston criteria v2.0 incorporate emerging MRI markers of CAA to enhance sensitivity without compromising their specificity in our cohorts of patients aged 50 years and older presenting with spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes. Future studies will be needed to determine generalisability of the v.2.0 criteria across the full range of patients and clinical presentations.FUNDING: US National Institutes of Health (R01 AG26484).
- Published
- 2021
- Full Text
- View/download PDF
4. Impact of Cerebral Amyloid Angiopathy in Two Transgenic Mouse Models of Cerebral β-Amyloidosis: A Neuropathological Study
- Author
-
Berta Paez, Paula Marazuela, Anna Bonaterra Pastra, Maria Mar Hernandez Guillamon, Montse Solé, Institut Català de la Salut, Laboratori de Recerca Neurovascular, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain, and Vall d'Hebron Barcelona Hospital Campus
- Subjects
Mice, Transgenic ,Plaque, Amyloid ,enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::trastornos cerebrovasculares::enfermedades arteriales intracraneales::enfermedades arteriales cerebrales::angiopatía amiloide cerebral [ENFERMEDADES] ,Catalysis ,Inorganic Chemistry ,Mice ,Alzheimer Disease ,Animals ,Amino Acids, Peptides, and Proteins::Peptides::Amyloid beta-Peptides [CHEMICALS AND DRUGS] ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,Amyloid beta-Peptides ,Organic Chemistry ,Brain ,Amyloidosis ,General Medicine ,Eukaryota::animales::grupos de población animal::animales modificados genéticamente::ratones transgénicos [ORGANISMOS] ,APP23 ,5xFAD ,cerebral β-amyloidosis ,preclinical MRI ,cerebral microbleeds ,Computer Science Applications ,Cerebral Amyloid Angiopathy ,Disease Models, Animal ,Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Cerebrovascular Disorders::Intracranial Arterial Diseases::Cerebral Arterial Diseases::Cerebral Amyloid Angiopathy [DISEASES] ,Amiloïdosi ,aminoácidos, péptidos y proteínas::péptidos::péptidos beta amiloides [COMPUESTOS QUÍMICOS Y DROGAS] ,Female ,Ratolins transgènics ,Malalties cerebrovasculars ,Eukaryota::Animals::Animal Population Groups::Animals, Genetically Modified::Mice, Transgenic [ORGANISMS] - Abstract
Microhemorragias cerebrales; Beta-amiloidosis cerebral; Resonancia magnética preclínica Cerebral microbleeds; Cerebral beta-amyloidosis; Preclinical MRI Microhemorràgies cerebrals; Beta-amiloidosi cerebral; Ressonància magnètica preclínica The pathological accumulation of parenchymal and vascular amyloid-beta (Aβ) are the main hallmarks of Alzheimer’s disease (AD) and Cerebral Amyloid Angiopathy (CAA), respectively. Emerging evidence raises an important contribution of vascular dysfunction in AD pathology that could partially explain the failure of anti-Aβ therapies in this field. Transgenic mice models of cerebral β-amyloidosis are essential to a better understanding of the mechanisms underlying amyloid accumulation in the cerebrovasculature and its interactions with neuritic plaque deposition. Here, our main objective was to evaluate the progression of both parenchymal and vascular deposition in APP23 and 5xFAD transgenic mice in relation to age and sex. We first showed a significant age-dependent accumulation of extracellular Aβ deposits in both transgenic models, with a greater increase in APP23 females. We confirmed that CAA pathology was more prominent in the APP23 mice, demonstrating a higher progression of Aβ-positive vessels with age, but not linked to sex, and detecting a pronounced burden of cerebral microbleeds (cMBs) by magnetic resonance imaging (MRI). In contrast, 5xFAD mice did not present CAA, as shown by the negligible Aβ presence in cerebral vessels and the occurrence of occasional cMBs comparable to WT mice. In conclusion, the APP23 mouse model is an interesting tool to study the overlap between vascular and parenchymal Aβ deposition and to evaluate future disease-modifying therapy before its translation to the clinic. This work was funded by the Instituto de Salud Carlos III (ISCIII), (PI20/00465) and co-financed by the European Regional Development Fund (FEDER). The Neurovascular Research Laboratory is part of the RICORS-ICTUS-Enfermedades Vasculares Cerebrales network, ISCIII, Spain (RD21/0006/0007).
- Published
- 2022
- Full Text
- View/download PDF
5. Role of PATJ in stroke prognosis by modulating endothelial to mesenchymal transition through the Hippo/Notch/PI3K axis
- Author
-
Aina Medina-Dols, Guillem Cañellas, Toni Capó, Montse Solé, Marina Mola-Caminal, Natalia Cullell, Marina Jaume, Laura Nadal-Salas, Jaume Llinàs, Lluis Gómez, Silvia Tur, Carmen Jiménez, Rosa M. Díaz, Caty Carrera, Elena Muiño, Cristina Gallego-Fabrega, Carolina Soriano-Tárraga, Laura Ruiz-Guerra, Josep Pol-Fuster, Víctor Asensio, Josep Muncunill, Aarne Fleischer, Amanda Iglesias, Eva Giralt-Steinhauer, Uxue Lazcano, Isabel Fernández-Pérez, Joan Jiménez-Balado, Marina Gabriel-Salazar, Miguel Garcia-Gabilondo, Ting Lei, Nuria-Paz Torres-Aguila, Jara Cárcel-Márquez, Jerònia Lladó, Gabriel Olmos, Anna Rosell, Joan Montaner, Anna M. Planas, Raquel Rabionet, Mar Hernández-Guillamon, Jordi Jiménez-Conde, Israel Fernández-Cadenas, and Cristòfol Vives-Bauzá
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Cytology ,QH573-671 - Abstract
Abstract Through GWAS studies we identified PATJ associated with functional outcome after ischemic stroke (IS). The aim of this study was to determine PATJ role in brain endothelial cells (ECs) in the context of stroke outcome. PATJ expression analyses in patient’s blood revealed that: (i) the risk allele of rs76221407 induces higher expression of PATJ, (ii) PATJ is downregulated 24 h after IS, and (iii) its expression is significantly lower in those patients with functional independence, measured at 3 months with the modified Rankin scale ((mRS) ≤2), compared to those patients with marked disability (mRS = 4–5). In mice brains, PATJ was also downregulated in the injured hemisphere at 48 h after ischemia. Oxygen-glucose deprivation and hypoxia-dependent of Hypoxia Inducible Factor-1α also caused PATJ depletion in ECs. To study the effects of PATJ downregulation, we generated PATJ-knockdown human microvascular ECs. Their transcriptomic profile evidenced a complex cell reprogramming involving Notch, TGF-ß, PI3K/Akt, and Hippo signaling that translates in morphological and functional changes compatible with endothelial to mesenchymal transition (EndMT). PATJ depletion caused loss of cell-cell adhesion, upregulation of metalloproteases, actin cytoskeleton remodeling, cytoplasmic accumulation of the signal transducer C-terminal transmembrane Mucin 1 (MUC1-C) and downregulation of Notch and Hippo signaling. The EndMT phenotype of PATJ-depleted cells was associated with the nuclear recruitment of MUC1-C, YAP/TAZ, β-catenin, and ZEB1. Our results suggest that PATJ downregulation 24 h after IS promotes EndMT, an initial step prior to secondary activation of a pro-angiogenic program. This effect is associated with functional independence suggesting that activation of EndMT shortly after stroke onset is beneficial for stroke recovery.
- Published
- 2024
- Full Text
- View/download PDF
6. Association of candidate genetic variants and circulating levels of ApoE/ApoJ with common neuroimaging features of cerebral amyloid angiopathy
- Author
-
Anna Bonaterra-Pastra, Sònia Benítez, Olalla Pancorbo, David Rodríguez-Luna, Carla Vert, Alex Rovira, M. Mar Freijo, Silvia Tur, Maite Martínez-Zabaleta, Pere Cardona Portela, Rocío Vera, Lucia Lebrato-Hernández, Juan F. Arenillas, Soledad Pérez-Sánchez, Ana Domínguez-Mayoral, Joan Martí Fàbregas, Gerard Mauri, Joan Montaner, Jose Luis Sánchez-Quesada, and Mar Hernández-Guillamon
- Subjects
ApoE ,ApoJ ,CAA ,MRI ,lipoproteins ,EPVS ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
IntroductionCerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid-β (Aβ) in brain vessels and is a main cause of lobar intracerebral hemorrhage (ICH) in the elderly. CAA is associated with magnetic resonance imaging (MRI) markers of small vessel disease (SVD). Since Aβ is also accumulated in Alzheimer’s disease (AD) in the brain parenchyma, we aimed to study if several single nucleotide polymorphisms (SNPs) previously associated with AD were also associated with CAA pathology. Furthermore, we also studied the influence of APOE and CLU genetic variants in apolipoprotein E (ApoE) and clusterin/apolipoprotein J (ApoJ) circulating levels and their distribution among lipoproteins.MethodsThe study was carried out in a multicentric cohort of 126 patients with lobar ICH and clinical suspicion of CAA.ResultsWe observed several SNPs associated with CAA neuroimaging MRI markers [cortical superficial siderosis (cSS), enlarged perivascular spaces in the centrum semiovale (CSO-EPVS), lobar cerebral microbleeds (CMB), white matter hyperintensities (WMH), corticosubcortical atrophy and CAA-SVD burden score]. Concretely, ABCA7 (rs3764650), CLU (rs9331896 and rs933188), EPHA1 (rs11767557), and TREML2 (rs3747742) were significantly associated with a CAA-SVD burden score. Regarding circulating levels of apolipoproteins, protective AD SNPs of CLU [rs11136000 (T) and rs9331896 (C)] were significantly associated with higher HDL ApoJ content in the lobar ICH cohort. APOEε2 carriers presented higher plasma and LDL-associated ApoE levels whereas APOEε4 carriers presented lower plasma ApoE levels. Additionally, we observed that lower circulating ApoJ and ApoE levels were significantly associated with CAA-related MRI markers. More specifically, lower LDL-associated ApoJ and plasma and HDL-associated ApoE levels were significantly associated with CSO-EPVS, lower ApoJ content in HDL with brain atrophy and lower ApoE content in LDL with the extent of cSS.DiscussionThis study reinforces the relevance of lipid metabolism in CAA and cerebrovascular functionality. We propose that ApoJ and ApoE distribution among lipoproteins may be associated with pathological features related to CAA with higher ApoE and ApoJ levels in HDL possibly enhancing atheroprotective, antioxidative, and anti-inflammatory responses in cerebral β-amyloidosis.
- Published
- 2023
- Full Text
- View/download PDF
7. Abstract WP305: Impact of Potential Systolic Blood Pressure Treatment Thresholds on Hematoma Growth in Acute Intracerebral Hemorrhage
- Author
-
David Rodriguez-Luna, Marta Rubiera, Marian Muchada, Pilar Coscojuela, Marc Ribo, Jorge Pagola, Alan Flores, Bernardo Ibarra, Pilar Meler, Estela Sanjuan, Mar Hernandez-Guillamon, Jose Alvarez-Sabin, Joan Montaner, and Carlos A Molina
- Subjects
Advanced and Specialized Nursing ,Neurology (clinical) ,Cardiology and Cardiovascular Medicine - Abstract
Background: Although the current AHA guidelines recommend maintaining systolic blood pressure (SBP) below 180 mmHg in acute intracerebral hemorrhage (ICH), little is known about the relationships between different therapeutic target thresholds and hematoma growth (HG). Therefore, we aimed to investigate the impact of potential SBP treatment thresholds on HG in patients with acute ICH. Methods: This study was a secondary analysis of data prospectively collected during a previously reported study of the impact of blood pressure (BP) on HG in 106 patients with acute ( Results: Patients who experienced HG (34%) presented higher SBP loads in all thresholds, reaching statistical significance in 170, 180, and 190 thresholds, but not in the others (Figure). Whilst SBP load thresholds were correlated neither with baseline nor 24-hour ICH volumes, highest (170 to 200) but not lowest (140 to 160) SBP load thresholds were significantly correlated with the amount of both relative and absolute hematoma enlargement at 24 hours (p Conclusions: In patients with acute supratentorial ICH, those who experience HG present higher SBP load from 140 to 200 mmHg thresholds. More intensive SBP-lowering treatment than guidelines recommendations is needed, at least below 170 mmHg, in order to minimize the deleterious effect of higher SBP on HG.
- Published
- 2013
- Full Text
- View/download PDF
8. MFG-E8 (LACTADHERIN): a novel marker associated with cerebral amyloid angiopathy
- Author
-
Paula Marazuela, Montse Solé, Anna Bonaterra-Pastra, Jesús Pizarro, Jessica Camacho, Elena Martínez-Sáez, H. Bea Kuiperij, Marcel M. Verbeek, Anna M. de Kort, Floris H. B. M. Schreuder, Catharina J. M. Klijn, Laura Castillo-Ribelles, Olalla Pancorbo, David Rodríguez-Luna, Francesc Pujadas, Pilar Delgado, and Mar Hernández-Guillamon
- Subjects
Cerebral amyloid angiopathy ,Alzheimer's disease ,Laser capture microdissection ,MFG-E8 ,Biomarkers ,Cerebrospinal fluid ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Brain accumulation of amyloid-beta (Aβ) is a crucial feature in Alzheimer´s disease (AD) and cerebral amyloid angiopathy (CAA), although the pathophysiological relationship between these diseases remains unclear. Numerous proteins are associated with Aβ deposited in parenchymal plaques and/or cerebral vessels. We hypothesized that the study of these proteins would increase our understanding of the overlap and biological differences between these two pathologies and may yield new diagnostic tools and specific therapeutic targets. We used a laser capture microdissection approach combined with mass spectrometry in the APP23 transgenic mouse model of cerebral-β-amyloidosis to specifically identify vascular Aβ-associated proteins. We focused on one of the main proteins detected in the Aβ-affected cerebrovasculature: MFG-E8 (milk fat globule-EGF factor 8), also known as lactadherin. We first validated the presence of MFG-E8 in mouse and human brains. Immunofluorescence and immunoblotting studies revealed that MFG-E8 brain levels were higher in APP23 mice than in WT mice. Furthermore, MFG-E8 was strongly detected in Aβ-positive vessels in human postmortem CAA brains, whereas MFG-E8 was not present in parenchymal Aβ deposits. Levels of MFG-E8 were additionally analysed in serum and cerebrospinal fluid (CSF) from patients diagnosed with CAA, patients with AD and control subjects. Whereas no differences were found in MFG-E8 serum levels between groups, MFG-E8 concentration was significantly lower in the CSF of CAA patients compared to controls and AD patients. Finally, in human vascular smooth muscle cells MFG-E8 was protective against the toxic effects of the treatment with the Aβ40 peptide containing the Dutch mutation. In summary, our study shows that MFG-E8 is highly associated with CAA pathology and highlights MFG-E8 as a new CSF biomarker that could potentially be used to differentiate cerebrovascular Aβ pathology from parenchymal Aβ deposition.
- Published
- 2021
- Full Text
- View/download PDF
9. New candidate blood biomarkers potentially associated with white matter hyperintensities progression
- Author
-
Joan Jiménez-Balado, Jesús Pizarro, Iolanda Riba-Llena, Anna Penalba, Júlia Faura, Elena Palà, Joan Montaner, Mar Hernández-Guillamon, and Pilar Delgado
- Subjects
Medicine ,Science - Abstract
Abstract We aimed to discover blood biomarkers associated with longitudinal changes in white matter hyperintensities (WMH). This study was divided into a discovery phase and a replication phase. Subjects in both studies were patients with hypertension, aged 50–70, who underwent two magnetic resonance imaging (MRI) sessions and blood extractions over a 4-year follow-up period. In the discovery phase, we screened 1305 proteins in 12 subjects with WMH progression and in 12 matched control subjects. We found that 41 proteins were differentially expressed: 13 were upregulated and 28 were downregulated. We subsequently selected three biomarkers for replication in baseline and follow-up samples in 80 subjects with WMH progression and in 80 control subjects. The selected protein candidates for the replication were MMP9 (matrix metalloproteinase-9), which was higher in cases, MET (hepatocyte growth factor receptor) and ASAH2 (neutral ceramidase), which were both lower in cases of WMH progression. Baseline biomarker concentrations did not predict WMH progression. In contrast, patients with WMH progression presented a steeper decline in MET over time. Furthermore, cases showed higher MMP9 and lower ASAH2 levels than controls at the follow-up. These results indicate that MMP9, MET, and ASAH2 are potentially associated with the progression of WMH, and could therefore be interesting candidates to validate in future studies.
- Published
- 2021
- Full Text
- View/download PDF
10. P4‐117: An Angiotensin‐Converting Enzyme (ACE) polymorphism is associated with intracerebral hemorrhage recurrences in Cerebral Amyloid Angiopathy patients
- Author
-
Joan Montaner, Sophie Domingues, Pablo Martinez-Lage, Isabel Hernández, Israel Fernández Cadenas, Mar Hernandez Guillamon, Pilar Delgado, Mireia Parés, and Mercè Boada
- Subjects
Intracerebral hemorrhage ,Pathology ,medicine.medical_specialty ,biology ,Epidemiology ,business.industry ,Health Policy ,Angiotensin-converting enzyme ,medicine.disease ,Ace polymorphism ,Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,medicine ,biology.protein ,Neurology (clinical) ,Cerebral amyloid angiopathy ,Geriatrics and Gerontology ,business - Published
- 2009
- Full Text
- View/download PDF
11. Peripheral administration of human recombinant ApoJ/clusterin modulates brain beta-amyloid levels in APP23 mice
- Author
-
Sofía Fernández de Retana, Paula Marazuela, Montse Solé, Guillem Colell, Anna Bonaterra, Jose Luis Sánchez-Quesada, Joan Montaner, Daniel Maspoch, Mary Cano-Sarabia, and Mar Hernández-Guillamon
- Subjects
Clusterin ,Apolipoprotein J ,ApoJ ,APP23 ,Reconstituted HDL ,Alzheimer’s disease ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background ApoJ/clusterin is a multifunctional protein highly expressed in the brain. The implication of ApoJ in β-amyloid (Aβ) fibrillization and clearance in the context of Alzheimer’s disease has been widely studied, although the source and concentration of ApoJ that promotes or inhibits Aβ cerebral accumulation is not clear yet. ApoJ is abundant in plasma and approximately 20% can appear bound to HDL-particles. In this regard, the impact of plasmatic ApoJ and its lipidation status on cerebral β-amyloidosis is still not known. Hence, our main objective was to study the effect of a peripheral increase of free ApoJ or reconstituted HDL particles containing ApoJ in an experimental model of cerebral β-amyloidosis. Methods Fourteen-month-old APP23 transgenic mice were subjected to subchronic intravenous treatment with rHDL-rApoJ nanodiscs or free rApoJ for 1 month. Aβ concentration and distribution in the brain, as well as Aβ levels in plasma and CSF, were determined after treatments. Other features associated to AD pathology, such as neuronal loss and neuroinflammation, were also evaluated. Results Both ApoJ-based treatments prevented the Aβ accumulation in cerebral arteries and induced a decrease in total brain insoluble Aβ42 levels. The peripheral treatment with rApoJ also induced an increase in the Aβ40 levels in CSF, whereas the concentration remained unaltered in plasma. At all the endpoints studied, the lipidation of rApoJ did not enhance the protective properties of free rApoJ. The effects obtained after subchronic treatment with free rApoJ were accompanied by a reduction in hippocampal neuronal loss and an enhancement of the expression of a phagocytic marker in microglial cells surrounding Aβ deposits. Finally, despite the activation of this phagocytic phenotype, treatments did not induce a global neuroinflammatory status. In fact, free rApoJ treatment was able to reduce the levels of interleukin-17 (IL17) and keratinocyte chemoattractant (KC) chemokine in the brain. Conclusions Our results demonstrate that an increase in circulating human rApoJ induces a reduction of insoluble Aβ and CAA load in the brain of APP23 mice. Thus, our study suggests that peripheral interventions, based on treatments with multifunctional physiological chaperones, offer therapeutic opportunities to regulate the cerebral Aβ load.
- Published
- 2019
- Full Text
- View/download PDF
12. Characterization of ApoJ-reconstituted high-density lipoprotein (rHDL) nanodisc for the potential treatment of cerebral β-amyloidosis
- Author
-
Sofía Fernández-de-Retana, Mary Cano-Sarabia, Paula Marazuela, Jose Luis Sánchez-Quesada, Annabel Garcia-Leon, Alex Montañola, Joan Montaner, Daniel Maspoch, and Mar Hernández-Guillamon
- Subjects
Medicine ,Science - Abstract
Abstract Cerebral β-amyloidosis is a major feature of Alzheimer’s disease (AD), characterized by the accumulation of β-amyloid protein (Aβ) in the brain. Several studies have implicated lipid/lipoprotein metabolism in the regulation of β-amyloidosis. In this regard, HDL (High Density Lipoprotein)-based therapies could ameliorate pathological features associated with AD. As apolipoprotein J (ApoJ) is a natural chaperone that interacts with Aβ, avoiding its aggregation and toxicity, in this study we propose to prepare reconstituted rHDL-rApoJ nanoparticles by assembling phospholipids with recombinant human ApoJ (rApoJ). Hence, rHDL particles were prepared using the cholate dialysis method and characterized by N-PAGE, dynamic light scattering, circular dichroism and electron transmission microscopy. The preparation of rHDL particles showed two-sized populations with discoidal shape. Functionally, rHDL-rApoJ maintained the ability to prevent the Aβ fibrillization and mediated a higher cholesterol efflux from cultured macrophages. Fluorescently-labelled rHDL-rApoJ nanoparticles were intravenously administrated in mice and their distribution over time was determined using an IVIS Xenogen® imager. It was confirmed that rHDL-rApoJ accumulated in the cranial region, especially in old transgenic mice presenting a high cerebral Aβ load. In conclusion, we have standardized a reproducible protocol to produce rHDL-rApoJ nanoparticles, which may be potentially considered as a therapeutic option for β-amyloid-related pathologies.
- Published
- 2017
- Full Text
- View/download PDF
13. Brain ApoA-I, ApoJ and ApoE Immunodetection in Cerebral Amyloid Angiopathy
- Author
-
Jessica Camacho, Teresa Moliné, Anna Bonaterra-Pastra, Santiago Ramón y Cajal, Elena Martínez-Sáez, and Mar Hernández-Guillamon
- Subjects
ApoE ,ApoA-I ,ApoJ ,clusterin ,β-amyloid ,cerebral amyloid angiopathy ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Cerebral amyloid angiopathy (CAA) is a common cause of lobar intracerebral hemorrhage (ICH) in elderly individuals and it is the result of the cerebrovascular deposition of beta-amyloid (Aβ) protein. CAA is frequently found in patients with Alzheimer's disease (AD), although it has an independent contribution to the cognitive deterioration associated with age. Specific apolipoproteins (Apo) have been associated with Aβ fibrillization and clearance from the brain. In this regard, in the present study, we analyzed the brain levels of ApoE, ApoA-I, and ApoJ/clusterin in autopsy brains from 20 post-mortem cases with CAA type I, CAA type II, with parenchymal Aβ deposits or without Aβ deposits. Our objective was to find a possible differential pattern of apolipoproteins distribution in the brain depending on the CAA pathological presentation. The protein expression levels were adjusted by the APOE genotype of the patients included in the study. We found that ApoE and ApoJ were abundantly present in meningeal, cortical, and capillary vessels of the brains with vascular Aβ accumulation. ApoE and ApoJ also deposited extracellularly in the parenchyma, especially in cases presenting Aβ diffuse and neuritic parenchymal deposits. In contrast, ApoA-I staining was only relevant in capillary walls in CAA type I cases. On the other hand, ICH was the principal cause of death among CAA patients in our cohort. We found that CAA patients with ICH more commonly had APOEε2 compared with CAA patients without ICH. In addition, patients who suffered an ICH presented higher vascular ApoE levels in brain. However, higher ApoE presence in cortical arteries was the only independent predictor of suffering an ICH in our cohort after adjusting by age and APOE genotype. In conclusion, while ApoE and ApoJ appear to be involved in both vascular and parenchymal Aβ pathology, ApoA-I seems to be mainly associated with CAA, especially in CAA type I pathology. We consider that our study helps to molecularly characterize the distribution subtypes of Aβ deposition within the brain.
- Published
- 2019
- Full Text
- View/download PDF
14. Survival Bias and Crosstalk between Chronological and Behavioral Age: Age- and Genotype-Sensitivity Tests Define Behavioral Signatures in Middle-Aged, Old, and Long-Lived Mice with Normal and AD-Associated Aging
- Author
-
Lydia Giménez-Llort, Daniela Marin-Pardo, Paula Marazuela, and Mar Hernández-Guillamón
- Subjects
survival ,aging ,Alzheimer’s disease ,heterogeneity ,long-life ,gait analysis ,Biology (General) ,QH301-705.5 - Abstract
New evidence refers to a high degree of heterogeneity in normal but also Alzheimer’s disease (AD) clinical and temporal patterns, increased mortality, and the need to find specific end-of-life prognosticators. This heterogeneity is scarcely explored in very old male AD mice models due to their reduced survival. In the present work, using 915 (432 APP23 and 483 C57BL/6 littermates) mice, we confirmed the better survival curves in male than female APP23 mice and respective wildtypes, providing the chance to characterize behavioral signatures in middle-aged, old, and long-lived male animals. The sensitivity of a battery of seven paradigms for comprehensive screening of motor (activity and gait analysis), neuropsychiatric and cognitive symptoms was analyzed using a cohort of 56 animals, composed of 12-, 18- and 24-month-old male APP23 mice and wildtype littermates. Most variables analyzed detected age-related differences. However, variables related to coping with stress, thigmotaxis, frailty, gait, and poor cognition better discriminated the behavioral phenotype of male APP23 mice through the three old ages compared with controls. Most importantly, non-linear age- and genotype-dependent behavioral signatures were found in long-lived animals, suggesting crosstalk between chronological and biological/behavioral ages useful to study underlying mechanisms and distinct compensations through physiological and AD-associated aging.
- Published
- 2021
- Full Text
- View/download PDF
15. Comparison of Plasma Lipoprotein Composition and Function in Cerebral Amyloid Angiopathy and Alzheimer’s Disease
- Author
-
Anna Bonaterra-Pastra, Sofia Fernández-de-Retana, Andrea Rivas-Urbina, Núria Puig, Sònia Benítez, Olalla Pancorbo, David Rodríguez-Luna, Francesc Pujadas, Maria del Mar Freijo, Silvia Tur, Maite Martínez-Zabaleta, Pere Cardona Portela, Rocío Vera, Lucia Lebrato-Hernández, Juan F. Arenillas, Soledad Pérez-Sánchez, Joan Montaner, Jose Luis Sánchez-Quesada, and Mar Hernández-Guillamon
- Subjects
cerebral amyloid angiopathy ,Alzheimer’s disease ,lipoprotein composition ,lipid profile ,apolipoproteins ,Biology (General) ,QH301-705.5 - Abstract
Cerebral amyloid angiopathy (CAA) refers to beta-amyloid (Aβ) deposition in brain vessels and is clinically the main cause of lobar intracerebral hemorrhage (ICH). Aβ can also accumulate in brain parenchyma forming neuritic plaques in Alzheimer’s disease (AD). Our study aimed to determine whether the peripheral lipid profile and lipoprotein composition are associated with cerebral beta-amyloidosis pathology and may reflect biological differences in AD and CAA. For this purpose, lipid and apolipoproteins levels were analyzed in plasma from 51 ICH-CAA patients (collected during the chronic phase of the disease), 60 AD patients, and 60 control subjects. Lipoproteins (VLDL, LDL, and HDL) were isolated and their composition and pro/antioxidant ability were determined. We observed that alterations in the lipid profile and lipoprotein composition were remarkable in the ICH-CAA group compared to control subjects, whereas the AD group presented no specific alterations compared with controls. ICH-CAA patients presented an atheroprotective profile, which consisted of lower total and LDL cholesterol levels. Plasma from chronic ICH-CAA patients also showed a redistribution of ApoC-III from HDL to VLDL and a higher ApoE/ApoC-III ratio in HDL. Whether these alterations reflect a protective response or have a causative effect on the pathology requires further investigation.
- Published
- 2021
- Full Text
- View/download PDF
16. Appearance of intra-nuclear matrix metalloproteinases is involved in the early stages of neuronal death following brain ischemia
- Author
-
Rosell, A., Cuadrado, E., Borrell-Pages, M., Navarro, M., Maria Mar Hernandez Guillamon, Penalba, A., Ortega, L., and Montaner, J.
17. Rat middle cerebral artery occlusion is not a suitable model for the study of stroke-induced spontaneous infections.
- Author
-
Mireia Campos-Martorell, Ma Ángeles Montero, Mar Hernández-Guillamón, Anna Rosell, Javier Gomis, David Salat, Lidia García-Bonilla, and Joan Montaner
- Subjects
Medicine ,Science - Abstract
BACKGROUND: Infections related to stroke-induced immunodepression are an important complication causing a high rate of death in patients. Several experimental studies in mouse stroke models have described this process but it has never been tested in other species such as rats. METHODS: Our study focused on the appearance of secondary systemic and pulmonary infections in ischemic rats, comparing with sham and naive animals. For that purpose, male Wistar rats were subjected to embolic middle cerebral artery occlusion (eMCAO) or to transient MCAO (tMCAO) inserting a nylon filament. Forty-eight hours after ischemia, blood and lung samples were evaluated. RESULTS: In eMCAO set, ischemic rats showed a significant decrease in blood-peripheral lymphocytes (naive = 58.8±18.1%, ischemic = 22.9±16.4%) together with an increase in polymorphonuclears (PMNs) (naive = 29.2±14.7%, ischemic = 71.7±19.5%), while no change in monocytes was observed. The increase in PMNs counts was positively correlated with worse neurological outcome 48 hours after eMCAO (r = 0.55, p = 0.043). However, sham animals showed similar changes in peripheral leukocytes as those seen in ischemic rats (lymphocytes: 40.1±19.7%; PMNs: 51.7±19.2%). Analysis of bacteriological lung growth showed clear differences between naive (0±0 CFU/mL; log10) and both sham (3.9±2.5 CFU/mL; log10) and ischemic (4.3±2.9 CFU/mL; log10) groups. Additionally, naive animals presented non-pathological lung histology, while both sham and ischemic showed congestion, edema or hemorrhage. Concordant results were found in the second set of animals submitted to a tMCAO. CONCLUSIONS: Inflammatory and infection changes in Wistar rats subjected to MCAO models may be attributed not only to the brain ischemic injury but to the surgical aggression and/or anaesthetic stress. Consequently, we suggest that stroke-induced immunodepression in ischemic experimental models should be interpreted with caution in further experimental and translational studies, at least in rat stroke models that entail cervicotomy and cranial trepanation.
- Published
- 2014
- Full Text
- View/download PDF
18. Factors secreted by endothelial progenitor cells enhance neurorepair responses after cerebral ischemia in mice.
- Author
-
Anna Rosell, Anna Morancho, Miriam Navarro-Sobrino, Elena Martínez-Saez, Mar Hernández-Guillamon, Silvia Lope-Piedrafita, Verónica Barceló, Francesc Borrás, Anna Penalba, Lidia García-Bonilla, and Joan Montaner
- Subjects
Medicine ,Science - Abstract
Cell therapy with endothelial progenitor cells (EPCs) has emerged as a promising strategy to regenerate the brain after stroke. Here, we aimed to investigate if treatment with EPCs or their secreted factors could potentiate angiogenesis and neurogenesis after permanent focal cerebral ischemia in a mouse model of ischemic stroke. BALB/C male mice were subjected to distal occlusion of the middle cerebral artery, and EPCs, cell-free conditioned media (CM) obtained from EPCs, or vehicle media were administered one day after ischemia. Magnetic resonance imaging (MRI) was performed at baseline to confirm that the lesions were similar between groups. Immunohistochemical and histological evaluation of the brain was performed to evaluate angio-neurogenesis and neurological outcome at two weeks. CM contained growth factors, such as VEGF, FGF-b and PDGF-bb. A significant increase in capillary density was noted in the peri-infarct areas of EPC- and CM-treated animals. Bielschowsky's staining revealed a significant increase in axonal rewiring in EPC-treated animals compared with shams, but not in CM-treated mice, in close proximity with DCX-positive migrating neuroblasts. At the functional level, post-ischemia forelimb strength was significantly improved in animals receiving EPCs or CM, but not in those receiving vehicle media. In conclusion, we demonstrate for the first time that the administration of EPC-secreted factors could become a safe and effective cell-free option to be considered in future therapeutic strategies for stroke.
- Published
- 2013
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.