Publications
150 results found
Sastre M, Gentleman S, Van Leuven F, 2018, TauBI or not TauBI: what was the question?, Brain, Vol: 141, Pages: 2536-2539, ISSN: 1460-2156
Sastre M, Edison P, Donat C, 2018, In vivo imaging of Glial activation in Alzheimer's disease, Frontiers in Neurology, Vol: 9, ISSN: 1664-2295
Alzheimer's disease (AD) is characterized by memory loss and decline of cognitive function, associated with progressive neurodegeneration. While neuropathological processes like amyloid plaques and tau neurofibrillary tangles have been linked to neuronal death in AD, the precise role of glial activation on disease progression is still debated. It was suggested that neuroinflammation could occur well ahead of amyloid deposition and may be responsible for clearing amyloid, having a neuroprotective effect; however, later in the disease, glial activation could become deleterious, contributing to neuronal toxicity. Recent genetic and preclinical studies suggest that the different activation states of microglia and astrocytes are complex, not as polarized as previously thought, and that the heterogeneity in their phenotype can switch during disease progression. In the last few years, novel imaging techniques e.g., new radiotracers for assessing glia activation using positron emission tomography and advanced magnetic resonance imaging technologies have emerged, allowing the correlation of neuro-inflammatory markers with cognitive decline, brain function and brain pathology in vivo. Here we review all new imaging technology in AD patients and animal models that has the potential to serve for early diagnosis of the disease, to monitor disease progression and to test the efficacy and the most effective time window for potential anti-inflammatory treatments.
Sastre M, Ries M, Solito E, 2018, The role of annexin A1 in the regulation of amyloid-β clearance and neuroinflammation in Alzheimer’s disease, World Congres on Neurology and metal disorders
Donat CK, Mirzaei N, Tang S-P, et al., 2018, Erratum to: Imaging of Microglial Activation in Alzheimer's Disease by [11C]PBR28 PET., Methods Mol Biol, Vol: 1750, Pages: E1-E1
Donat C, Mirzaei N, Tang S-P, et al., 2018, Imaging of Microglial Activation in Alzheimer's Disease by [11C]PBR28 PET, Biomarkers for Alzheimer's disease drug development, Editors: Perneczky, Publisher: Humana Press, Pages: 323-339
Donat CK, Mirzaei N, Tang S-P, et al., 2018, Imaging of Microglial Activation in Alzheimer's Disease by [11C]PBR28 PET., Methods Mol Biol, Vol: 1750, Pages: 323-339
Deficits in neuronal function and synaptic plasticity in Alzheimer's disease (AD) are believed to be linked to microglial activation. A hallmark of reactive microglia is the upregulation of mitochondrial translocator protein (TSPO) expression. Positron emission tomography (PET) is a nuclear imaging technique that measures the distribution of trace doses of radiolabeled compounds in the body over time. PET imaging using the 2nd generation TSPO tracer [11C]PBR28 provides an opportunity for accurate visualization and quantification of changes in microglial density in transgenic mouse models of Alzheimer's disease (AD). Here, we describe the methodology for the in vivo use of [11C]PBR28 in AD patients and the 5XFAD transgenic mouse model of AD and compare the results against healthy individuals and wild-type controls. To confirm the results, autoradiography with [3H]PBR28 and immunochemistry was carried out in the same mouse brains. Our data shows that [11C]PBR28 is suitable as a tool for in vivo monitoring of microglial activation and may be useful to assess treatment response in future studies.
Goldfinger M, Tilley B, Mediratta S, et al., 2018, Boxing and the brain: disruption of the neurovascular unit in chronic traumatic encephalopathy, 119th Meeting of the British-Neuropathological-Society (BNS) / Epilepsy Neuropathology Symposium, Publisher: WILEY, Pages: 29-29, ISSN: 0305-1846
Sidoryk-Wegrzynowicz M, Gerber YN, Ries M, et al., 2017, Astrocytes in mouse models of tauopathies acquire early deficits and lose neurosupportive functions, Acta Neuropathologica Communications, Vol: 5, ISSN: 2051-5960
Microtubule-associated protein tau aggregates constitute the characteristic neuropathological features of severalneurodegenerative diseases grouped under the name of tauopathies. It is now clear that the process of tauaggregation is associated with neurodegeneration. Several transgenic tau mouse models have been developed wheretau progressively aggregates, causing neuronal death. Previously we have shown that transplantation of astrocytes inP301S tau transgenic mice rescues cortical neuron death, implying that the endogenous astrocytes are deficient insurvival support. We now show that the gliosis markers Glial fibrillary acidic protein (GFAP) and S100 calcium-bindingprotein B (S100β) are elevated in brains from P301S tau mice compared to control C57Bl/6 mice whereas theexpression of proteins involved in glutamine/glutamate metabolism are reduced, pointing to a functional deficit. Totest whether astrocytes from P301S mice are intrinsically deficient, we co-cultured astrocytes and neurons from controland P301S mice. Significantly more C57-derived and P301S-derived neurons survived when cells were cultured withC57-derived astrocytes or astrocyte conditioned medium (C57ACM) than with P301S-derived astrocytes or astrocyteconditioned medium (P301SACM), or ACM from P301L tau mice, where the transgene is also specifically expressed inneurons. The astrocytic alterations developed in mice during the first postnatal week of life. In addition, P301SACMsignificantly decreased presynaptic (synaptophysin, SNP) and postsynaptic (postsynaptic density protein 95, PSD95)protein expression in cortical neuron cultures whereas C57ACM enhanced these markers. Since thrombospondin 1(TSP-1) is a major survival and synaptogenic factor, we examined whether TSP-1 is deficient in P301S mouse brains andACM. Significantly less TSP-1 was expressed in the brains of P301S tau mice or produced by P301S-derived astrocytes,whereas supplementation of P301SACM with TSP-1 increased its neurosupportiv
Donat CK, Scott G, Gentleman S, et al., 2017, Microglial activation in traumatic brain injury, Frontiers in Aging Neuroscience, Vol: 9, ISSN: 1663-4365
Microglia have a variety of functions in the brain, including synaptic pruning, CNS repair and mediating the immune response against peripheral infection. Microglia rapidly become activated in response to CNS damage. Depending on the nature of the stimulus, microglia can take a number of activation states, which correspond to altered microglia morphology, gene expression and function. It has been reported that early microglia activation following traumatic brain injury (TBI) may contribute to the restoration of homeostasis in the brain. On the other hand, if they remain chronically activated, such cells display a classically activated phenotype, releasing pro-inflammatory molecules, resulting in further tissue damage and contributing potentially to neurodegeneration. However, new evidence suggests that this classification is over-simplistic and the balance of activation states can vary at different points. In this article, we review the role of microglia in TBI, analyzing their distribution, morphology and functional phenotype over time in animal models and in humans. Animal studies have allowed genetic and pharmacological manipulations of microglia activation, in order to define their role. In addition, we describe investigations on the in vivo imaging of microglia using translocator protein (TSPO) PET and autoradiography, showing that microglial activation can occur in regions far remote from sites of focal injuries, in humans and animal models of TBI. Finally, we outline some novel potential therapeutic approaches that prime microglia/macrophages toward the beneficial restorative microglial phenotype after TBI.
Katsouri L, Lim YM, Eleftheriadou I, et al., 2016, PGC-1 alpha overexpression by lentiviral vector attenuates amyloid-beta load and neuronal loss in an Alzheimer's disease model, Conference on Changing the Face of Modern Medicine - Stem Cells and Gene Therapy, Publisher: MARY ANN LIEBERT, INC, Pages: A27-A27, ISSN: 1043-0342
Katsouri L, Lim YM, Blondrath K, et al., 2016, PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model, Proceedings of the National Academy of Sciences of USA, Vol: 113, Pages: 12292-12297, ISSN: 0027-8424
Current therapies for Alzheimer’s disease (AD) are symptomatic and do not target the underlying Aβ pathology and other important hallmarks including neuronal loss. PPARγ-coactivator-1α (PGC-1α) is a cofactor for transcription factors including the peroxisome proliferator-activated receptor-γ (PPARγ), and it is involved in the regulation of metabolic genes, oxidative phosphorylation, and mitochondrial biogenesis. We previously reported that PGC-1α also regulates the transcription of β-APP cleaving enzyme (BACE1), the main enzyme involved in Aβ generation, and its expression is decreased in AD patients. We aimed to explore the potential therapeutic effect of PGC-1α by generating a lentiviral vector to express human PGC-1α and target it by stereotaxic delivery to hippocampus and cortex of APP23 transgenic mice at the preclinical stage of the disease. Four months after injection, APP23 mice treated with hPGC-1α showed improved spatial and recognition memory concomitant with a significant reduction in Aβ deposition, associated with a decrease in BACE1 expression. hPGC-1α overexpression attenuated the levels of proinflammatory cytokines and microglial activation. This effect was accompanied by a marked preservation of pyramidal neurons in the CA3 area and increased expression of neurotrophic factors. The neuroprotective effects were secondary to a reduction in Aβ pathology and neuroinflammation, because wild-type mice receiving the same treatment were unaffected. These results suggest that the selective induction of PGC-1α gene in specific areas of the brain is effective in targeting AD-related neurodegeneration and holds potential as therapeutic intervention for this disease.
Sastre M, Ries M, Loiola R, et al., 2016, The anti-inflammatory Annexin A1 induces the clearance and degradation of the Amyloid-β peptide, Journal of Neuroinflammation, Vol: 13, ISSN: 1742-2094
Background: The toxicity of amyloid-β (Aβ) peptide present in the brain of Alzheimer’s disease (AD) patients is thought to be mediated via the increased secretion of pro-inflammatory mediators, which can lead to neuronal dysfunction and cell death. In addition, we have previously shown that inflammation can affect Aβ generation. More recently, we have reported that in vitro administration of the anti-inflammatory mediator Annexin A1 (ANXA1) following an inflammatory challenge suppressed microglial activation and this effect was mediated through Formyl Peptide Receptor Like-1 (FPRL1/FPR2) signalling. The aim of this study was to determine the potential role of ANXA1 in the generation and clearance of Aβ. Methods: We first compared ANXA1 protein expression in the brains of AD patients and healthy controls as well as in the 5XFAD model of AD. To determine the role of ANXA1 in the processing of amyloid precursor protein (APP) and the degradation of Aβ, N2a neuroblastoma cells were treated with human recombinant ANXA1 or transfected with ANXA1 siRNA. We also investigated the effect of ANXA1 on Aβ phagocytosis and microglial activation in BV2 cells treated with synthetic Aβ. Results: Our data show that ANXA1 is increased in the brains of AD patients and animal models of AD at early stages. ANXA1 was able to reduce the levels of Aβ by increasing its enzymatic degradation by neprilysin in N2a cells and to stimulate Aβ phagocytosis by microglia. These effects were mediated through FPRL1 receptors. In addition, ANXA1 inhibited the Aβ-stimulated secretion of inflammatory mediators by microglia. Conclusions: These data suggest that ANXA1 plays a pivotal role in Aβ clearance and supports the use of ANXA1 as potential pharmacological tool for AD therapeutics.
Birch A, Cheung J, Oluwadare C, et al., 2016, Alterations in the expression of transcription factors PPARγ and NFκB in the brain of models of chronic pain, Biochemistry and Pharmacology, Vol: 5, ISSN: 2167-0501
Blondrath K, Steel JH, Katsouri L, et al., 2016, The nuclear cofactor receptor interacting protein-140 (RIP140) regulates the expression of genes involved in Aβ generation, Neurobiology of Aging, Vol: 47, Pages: 180-191, ISSN: 1558-1497
The Receptor Interacting Protein 140 (RIP140) is a cofactor for several nuclear receptors and has been involved in the regulation of metabolic and inflammatory genes. We hypothesize that RIP140 may also affect Aβ generation because it modulates the activity of transcription factors previously implicated in APP processing, such as PPARγ. We found that the levels of RIP140 are reduced in AD post-mortem brains compared with healthy controls. In addition, in situ hybridization experiments revealed that RIP140 expression is enriched in the same brain areas involved in AD pathology, such as cortex and hippocampus. Furthermore, we provide evidence using cell lines and genetically modified mice that RIP140 is able to modulate the transcription of certain genes involved in AD pathology, such as BACE1 and GSK3. Consequently, we found that RIP140 overexpression reduced the generation of Aβ in a neuroblastoma cell line by decreasing the transcription of BACE1 via a PPARγ-dependent mechanism. The results of this study therefore provide molecular insights into common signalling pathways linking metabolic disease with AD.
Feeney C, Scott GP, Cole JH, et al., 2016, Seeds of neuroendocrine doubt, Nature, Vol: 535, Pages: E1-E2, ISSN: 0028-0836
Sastre M, Ries M, 2016, Mechanisms of Aβ clearance and degradation by glial cells, Frontiers in Aging Neuroscience, Vol: 8, ISSN: 1663-4365
Tang SP, Mirzaei N, Coello C, et al., 2016, EVALUATION OF [11C]PBR28 PET IMAGING TO DETECT CHANGES IN MICROGLIAL ACTIVATION IN MOUSE MODELS OF ALZHEIMER'S DISEASE, 27th International Symposium on Cerebral Blood Flow, Metabolism and Function / 12th International Conference on Quantification of Brain Function with PET, Publisher: SAGE PUBLICATIONS INC, Pages: 654-655, ISSN: 0271-678X
Mirzaei N, de Burgh R, Sharp D, et al., 2016, Evaluation of [3H]PBR28 as a marker of microglial activation in the rat controlled cortical impact model of traumatic brain injury, International Brain Injury Association’s Eleventh World Congress on Brain Injury, Publisher: Taylor & Francis, Pages: 608-608, ISSN: 1362-301X
Parr C, Carzaniga R, Gentleman SM, et al., 2016, Glycogen Synthase Kinase 3 Inhibition Promotes Lysosomal Biogenesis and Autophagic Degradation of the Amyloid-beta Precursor Protein (vol 32, pg 4410, 2012), Molecular and Cellular Biology, Vol: 36, ISSN: 1098-5549
Mirzaei N, Tang SP, Ashworth S, et al., 2016, In vivo imaging of microglial activation by positron emission tomography with [11 C]PBR28 in the 5XFAD model of Alzheimer's disease, GLIA, ISSN: 0894-1491
Microglial activation has been linked with deficits in neuronal function and synaptic plasticity in Alzheimer's disease (AD). The mitochondrial translocator protein (TSPO) is known to be upregulated in reactive microglia. Accurate visualization and quantification of microglial density by PET imaging using the TSPO tracer [11C]-R-PK11195 has been challenging due to the limitations of the ligand. In this study, it was aimed to evaluate the new TSPO tracer [11C]PBR28 as a marker for microglial activation in the 5XFAD transgenic mouse model of AD. Dynamic PET scans were acquired following intravenous administration of [11C]PBR28 in 6-month-old 5XFAD mice and in wild-type controls. Autoradiography with [3H]PBR28 was carried out in the same brains to further confirm the distribution of the radioligand. In addition, immunohistochemistry was performed on adjacent brain sections of the same mice to evaluate the co-localization of TSPO with microglia. PET imaging revealed that brain uptake of [11C]PBR28 in 5XFAD mice was increased compared with control mice. Moreover, binding of [3H]PBR28, measured by autoradiography, was enriched in cortical and hippocampal brain regions, coinciding with the positive staining of the microglial marker Iba-1 and amyloid deposits in the same areas. Furthermore, double-staining using antibodies against TSPO demonstrated co-localization of TSPO with microglia and not with astrocytes in 5XFAD mice and human post-mortem AD brains. The data provided support of the suitability of [11C]PBR28 as a tool for in vivo monitoring of microglial activation and assessment of treatment response in future studies using animal models of AD
Mirzaei N, Tang S, Ashworth S, et al., 2016, In vivo Imaging of microglial activation by positron emission tomography with [11C]PBR28 in the 5XFAD model of Alzheimer’s disease, GLIA, ISSN: 0894-1491
Microglial activation has been linked with deficits in neuronal function and synaptic plasticity inAlzheimer’s disease (AD). The mitochondrial translocator protein (TSPO) is known to be upregulatedin reactive microglia. Accurate visualization and quantification of microglial density by PET imagingusing the TSPO tracer [11C]-R-PK11195 has been challenging due to the limitations of the ligand. Inthis study, we aimed to evaluate the new TSPO tracer [11C]PBR28 as a marker for microglialactivation in the 5XFAD transgenic mouse model of AD. Dynamic PET scans were acquired followingintravenous administration of [11C]PBR28 in 6 month old 5XFAD mice and in wild-type controls.Autoradiography with [3H]PBR28 was carried out in the same brains to further confirm thedistribution of the radioligand. In addition, immunohistochemistry was performed on adjacent brainsections of the same mice to evaluate the co-localization of TSPO with microglia. PET imagingrevealed that brain uptake of [11C]PBR28 in 5XFAD mice was increased compared with control mice.Moreover, binding of [3H]PBR28, measured by autoradiography, was enriched in cortical andhippocampal brain regions, coinciding with the positive staining of the microglial marker Iba-1 andamyloid deposits in the same areas. Furthermore, double-staining using antibodies against TSPOdemonstrated co-localization of TSPO with microglia and not with astrocytes in 5XFAD mice andhuman post-mortem AD brains. Our data provide support of the suitability of [11C]PBR28 as a tool forin vivo monitoring of microglial activation and assessment of treatment response in future studiesusing animal models of AD.
Sastre M, Ritchie CW, Hajji N, 2015, Metal Ions in Alzheimer’s disease brain, JSM Alzheimer’s Disease and Related Dementia, Vol: 2
There is substantial evidence supporting a critical role for metal ions in thepathogenesis of Alzheimer’s disease (AD). This originated with the observation thatcertain metal ions (principally copper, iron and zinc) are enriched in the neuriticplaques of AD brains, leading to an overall reduction in their bioavailability, suchas in the synaptic cleft. Imbalances of metal ions associated with aging and AD mayaffect the disease progression, leading to metals being reduced or increased fromtheir physiological steady state. Because metals ions are essential cofactors for manyproteins and they can compete with each other for binding to proteins, it is essentialto maintain metal homeostasis in order to preserve neuronal function. Some heavymetals may aggravate the progression of the disease due to their high neurotoxicityand their ability to induce epigenetic changes. On the other hand, alterations inthe levels of certain metal ions in other compartments in the brain could affect Aβenzymatic degradation, increase Aβ and tau aggregation as well as the processing ofthe amyloid precursor protein (APP) and other intracellular processes. Metal ions arealso instrumental in enhancing the production of reactive oxygen species in the brain,which could have consequences for neuronal viability and function. Here we review thestudies reporting the concentrations in brain, CSF and plasma in AD patients and howalterations in their transport and storage mechanisms can lead to their redistribution inthe brain, contributing to AD neuropathology.
Katsouri L, Ashraf A, Birch AM, et al., 2015, Systemic administration of fibroblast growth factor-2 (FGF2) reduces BACE1 expression and amyloid pathology in APP23 mice, NEUROBIOLOGY OF AGING, Vol: 36, Pages: 821-831, ISSN: 0197-4580
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- Citations: 31
Parr C, Mirzaei N, Christian M, et al., 2014, Activation of the Wnt/β-catenin pathway represses the transcription of the β-amyloid precursor protein cleaving enzyme (BACE1) via binding of T-cell factor-4 to BACE1 promoter, The FASEB Journal, ISSN: 0892-6638
Blondrath K, Sastre M, 2014, The ppargamma cofactor RIP140 regulates BACE1 gene expression, Publisher: Elsevier, ISSN: 1552-5279
Katsouri L, Lim YM, Mazarakis N, et al., 2014, PGC-1α gene therapy improves memory and decreases amyloid beta in APP23 mice, Publisher: Elsevier, ISSN: 1552-5279
Mirzaei N, Parr C, Christian M, et al., 2014, Activation of the WNT/B-catenin pathway represses the transcription of the B-APP cleaving enzyme (BACE1), Publisher: Elsevier, ISSN: 1552-5279
Torres M, Price SL, Fiol-deRoque MA, et al., 2014, Membrane lipid modifications and therapeutic effects mediated by hydroxydocosahexaenoic acid on Alzheimer's disease, BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, Vol: 1838, Pages: 1680-1692, ISSN: 0005-2736
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- Citations: 45
Birch AM, Katsouri L, Sastre M, 2014, Modulation of inflammation in transgenic models of Alzheimer's disease, JOURNAL OF NEUROINFLAMMATION, Vol: 11, ISSN: 1742-2094
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- Citations: 90
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