142 results found
Vilar R, Priessner M, Summers PA, et al., 2021, Selective detection of Cu+ ions in live cells via fluorescence lifetime imaging microscopy., Angewandte Chemie International Edition, ISSN: 1433-7851
Copper is an essential trace element in living organisms with its levels and localisation being carefully managed by the cellular machinery. However, if misregulated, deficiency or excess of copper ions can lead to several diseases. Therefore, it is important to have reliable methods to detect, monitor and visualise this metal in cells. Herein we report a new optical probe based on BODIPY, which shows a switch-on in its fluorescence intensity upon binding to copper(I), but not in the presence of high concentration of other physiologically relevant metal ions. More interestingly, binding to copper(I) leads to significant changes in the fluorescence lifetime of the new probe, which can be used to visualize copper(I) pools in lysosomes of live cells via fluorescence lifetime imaging microscopy (FLIM).
Mirzaei N, Davis N, Chau TW, et al., 2021, Astrocyte reactivity in Alzheimer’s disease; therapeutic opportunities to promote repair, Current Alzheimer Research, ISSN: 1567-2050
Astrocytes are fast climbing the ladder of importance in neurodegenerative disorders, particularly in Alzheimer’s disease (AD), with the prominent presence of reactive astrocytes surrounding amyloid β- plaques, together with activated microglia. Reactive astrogliosis, implying morphological and molecular transformations in astrocytes, seems to precede neurodegeneration, suggesting a role in the development of the disease. Single-cell transcriptomics have recently demonstrated that astrocytes from AD brains are different from “normal” healthy astrocytes, showing dysregulations in areas such as neurotransmitter recycling, including glutamate and GABA, and impaired homeostatic functions. However, recent data suggests that the ablation of astrocytes in mouse models of amyloidosis results in an increase in amyloid pathology as well as in the inflammatory profile and reduced synaptic density, indicating that astrocytes mediate neuroprotective effects. The idea that interventions targeting astrocytes may have great potential for AD has therefore emerged, supported by a range of drugs and stem cell transplantation studies that have successfully shown a therapeutic effect in mouse models of AD. In this article, we review the latest reports on the role and profile of astrocytes in AD brains and how manipulation of astrocytes in animal models has paved the way for the use of treatments enhancing astrocytic function as future therapeutic avenues for AD.
Calsolaro V, Matthews PM, Donat CK, et al., 2021, Astrocyte reactivity with late onset cognitive impairment assessed in-vivo using 11C-BU99008 PET and its relationship with amyloid load, Molecular Psychiatry, ISSN: 1359-4184
11C-BU99008 is a novel positron emission tomography (PET) tracer that enables selective imaging of astrocyte reactivity in vivo. To explore astrocyte reactivity associated with Alzheimer’s disease, 11 older, cognitively impaired (CI) subjects and 9 age-matched healthy controls (HC) underwent 3T magnetic resonance imaging (MRI), 18F-florbetaben and 11C-BU99008 PET. The 8 amyloid (Aβ)-positive CI subjects had higher 11C-BU99008 uptake relative to HC across the whole brain, but particularly in frontal, temporal, medial temporal and occipital lobes. Biological parametric mapping demonstrated a positive voxel-wise neuroanatomical correlation between 11C-BU99008 and 18F-florbetaben. Autoradiography using 3H-BU99008 with post-mortem Alzheimer’s brains confirmed through visual assessment that increased 3H-BU99008 binding localised with the astrocyte protein glial fibrillary acid protein and was not displaced by PiB or florbetaben. This proof-of-concept study provides direct evidence that 11C-BU99008 can measure in vivo astrocyte reactivity in people with late-life cognitive impairment and Alzheimer’s disease. Our results confirm that increased astrocyte reactivity is found particularly in cortical regions with high Aβ load. Future studies now can explore how clinical expression of disease varies with astrocyte reactivity.
Farajzadeh Khosroshahi S, Yin X, Donat C, et al., 2021, Multiscale modelling of cerebrovascular injury reveals the role of vascular anatomy and parenchymal shear stresses, Scientific Reports, Vol: 11, ISSN: 2045-2322
Neurovascular injury is often observed in traumatic brain injury (TBI). However, the relationship between mechanical forces and vascular injury is still unclear. A key question is whether the complex anatomy of vasculature plays a role in increasing forces in cerebral vessels and producing damage. We developed a high-fidelity multiscale finite element model of the rat brain featuring a detailed definition of the angioarchitecture. Controlled cortical impacts were performed experimentally and in-silico. The model was able to predict the pattern of blood–brain barrier damage. We found strong correlation between the area of fibrinogen extravasation and the brain area where axial strain in vessels exceeds 0.14. Our results showed that adjacent vessels can sustain profoundly different axial stresses depending on their alignment with the principal direction of stress in parenchyma, with a better alignment leading to larger stresses in vessels. We also found a strong correlation between axial stress in vessels and the shearing component of the stress wave in parenchyma. Our multiscale computational approach explains the unrecognised role of the vascular anatomy and shear stresses in producing distinct distribution of large forces in vasculature. This new understanding can contribute to improving TBI diagnosis and prevention.
Palmer EOC, Ward G, Mota B, et al., 2021, ALCOHOL HANGOVER INDUCES INCREASED NEUROINFLAMMATORY RESPONSE IN A RODENT MODEL, Publisher: WILEY, Pages: 202A-203A, ISSN: 0145-6008
Mota B, Sastre M, 2021, The role of PGC1α in Alzheimer’s disease and therapeutic interventions, International Journal of Molecular Sciences, Vol: 22, ISSN: 1422-0067
The peroxisome proliferator-activated receptor co-activator-1α (PGC1α) belongs to a family of transcriptional regulators, which act as co-activators for a number of transcription factors, including PPARs, NRFs, oestrogen receptors, etc. PGC1α has been implicated in the control of mitochondrial biogenesis, the regulation of the synthesis of ROS and inflammatory cytokines, as well as genes controlling metabolic processes. The levels of PGC1α have been shown to be altered in neurodegenerative disorders. In the brains of Alzheimer’s disease (AD) patients and animal models of amyloidosis, PGC1α expression was reduced compared with healthy individuals. Recently, it was shown that overexpression of PGC1α resulted in reduced amyloid-β (Aβ) generation, particularly by regulating the expression of BACE1, the rate-limiting enzyme involved in the production of Aβ. These results provide evidence pointing toward PGC1α activation as a new therapeutic avenue for AD, which has been supported by the promising observations of treatments with drugs that enhance the expression of PGC1α and gene therapy studies in animal models of AD. This review summarizes the different ways and mechanisms whereby PGC1α can be neuroprotective in AD and the pre-clinical treatments that have been explored so far.
Ries M, Watts H, Mota B, et al., 2021, Annexin-A1 restores cerebrovascular integrity concomitant with reduced amyloid-β and tau pathology, Brain: a journal of neurology, Vol: 144, Pages: 1526-1541, ISSN: 0006-8950
Alzheimer’s disease (AD), characterized by brain deposits of amyloid-β(Aβ) plaques and neurofibrillary tangles, is also linked to neurovascular dysfunction and blood-brain barrier (BBB) breakdown, affecting the passage of substances into and out of the brain. We hypothesized that treatment of neurovascular alterations could be beneficial in AD. Annexin A1 (ANXA1) is a mediator of glucocorticoids anti-inflammatory action that can suppress microglial activation and reduce BBB leakage. We have reported recently that treatment with recombinant human ANXA1 (hrANXA1) 2reduced Aβ levels by increased degradation in neuroblastoma cells and phagocytosis by microglia. Here, we show the beneficial effects of hrANXA1 in vivo by restoring efficient BBB function and decreasing Aβ and tau pathology in 5xFAD mice and Tau-P301L mice. We demonstrate that young 5xFAD mice already suffer cerebrovascular damage, while acute pre-administration of hrANXA1 rescued the vascular defects. Interestingly, the ameliorated BBB permeability in young 5xFAD mice by hrANXA1 correlated with reduced brain A load, due to increased clearance and degradation of Aβ by the insulin degrading enzyme (IDE). The systemic anti-inflammatory properties of hrANXA1 were also observed in 5XFAD mice, increasing IL-10 and reducing TNF-α expression. Additionally, the prolonged treatment with hrANXA1 reduced the memory deficits and increased synaptic density in young 5xFAD mice. Similarly, in Tau-P301L mice, acute hrANXA1 administration restored vascular architecture integrity, affecting the distribution of tight junctions, and reduced tau phosphorylation. The combined data support the hypothesis that the BBB breakdown early in AD can be restored by hrANXA1 as a potential therapeutic approach.
Rejc L, Gómez-Vallejo V, Joya A, et al., 2021, Longitudinal evaluation of a novel BChE PET tracer as an early in vivo biomarker in the brain of a mouse model for Alzheimer disease, Theranostics, Vol: 11, Pages: 6524-6559, ISSN: 1838-7640
Purpose: The increase in butyrylcholinesterase (BChE) activity in the brain of Alzheimer disease (AD) patients and animal models of AD position this enzyme as a potential biomarker of the disease. However, the information on the ability of BChE to serve as AD biomarker is contradicting, also due to scarce longitudinal studies of BChE activity abundance. Here, we report 11C-labeling, in vivo stability, biodistribution, and longitudinal study on BChE abundance in the brains of control and 5xFAD (AD model) animals, using a potent BChE selective inhibitor, [11C]4, and positron emission tomography (PET) in combination with computerised tomography (CT). We correlate the results with in vivo amyloid beta (Aβ) deposition, longitudinally assessed by [18F]florbetaben-PET imaging.Methods: [11C]4 was radiolabelled through 11C-methylation. Metabolism studies were performed on blood and brain samples of female wild type (WT) mice. Biodistribution studies were performed in female WT mice using dynamic PET-CT imaging. Specific binding was demonstrated by ex vivo and in vivo PET imaging blocking studies in female WT and 5xFAD mice at the age of 7 months. Longitudinal PET imaging of BChE was conducted in female 5xFAD mice at 4, 6, 8, 10 and 12 months of age and compared to age-matched control animals. Additionally, Aβ plaque distribution was assessed in the same mice using [18F]florbetaben at the ages of 2, 5, 7 and 11 months. The results were validated by ex vivo staining of BChE at 4, 8, and 12 months and Aβ at 12 months on brain samples.Results: [11C]4 was produced in sufficient radiochemical yield and molar activity for the use in PET imaging. Metabolism and biodistribution studies confirmed sufficient stability in vivo, the ability of [11C]4 to cross the blood brain barrier (BBB) and rapid washout from the brain. Blocking studies confirmed specificity of the binding. Longitudinal PET studies showed increased levels of BChE in the cerebral cortex, hippocampus, stri
Davis N, Mota BC, Stead L, et al., 2021, Pharmacological ablation of astrocytes reduces Aβ degradation and synaptic connectivity in an ex vivo model of Alzheimer's disease, Journal of Neuroinflammation, Vol: 18, ISSN: 1742-2094
BackgroundAstrocytes provide a vital support to neurons in normal and pathological conditions. In Alzheimer’s disease (AD) brains, reactive astrocytes have been found surrounding amyloid plaques, forming an astrocytic scar. However, their role and potential mechanisms whereby they affect neuroinflammation, amyloid pathology, and synaptic density in AD remain unclear.MethodsTo explore the role of astrocytes on Aβ pathology and neuroinflammatory markers, we pharmacologically ablated them in organotypic brain culture slices (OBCSs) from 5XFAD mouse model of AD and wild-type (WT) littermates with the selective astrocytic toxin L-alpha-aminoadipate (L-AAA). To examine the effects on synaptic circuitry, we measured dendritic spine number and size in OBCSs from Thy-1-GFP transgenic mice incubated with synthetic Aβ42 or double transgenics Thy-1-GFP/5XFAD mice treated with LAAA or vehicle for 24 h.ResultsTreatment of OBCSs with L-AAA resulted in an increased expression of pro-inflammatory cytokine IL-6 in conditioned media of WTs and 5XFAD slices, associated with changes in microglia morphology but not in density. The profile of inflammatory markers following astrocytic loss was different in WT and transgenic cultures, showing reductions in inflammatory mediators produced in astrocytes only in WT sections. In addition, pharmacological ablation of astrocytes led to an increase in Aβ levels in homogenates of OBCS from 5XFAD mice compared with vehicle controls, with reduced enzymatic degradation of Aβ due to lower neprilysin and insulin-degrading enzyme (IDE) expression. Furthermore, OBSCs from wild-type mice treated with L-AAA and synthetic amyloid presented 56% higher levels of Aβ in culture media compared to sections treated with Aβ alone, concomitant with reduced expression of IDE in culture medium, suggesting that astrocytes contribute to Aβ clearance and degradation. Quantification of hippocampal dendritic spines revealed a reducti
Mirzaei N, Mota B, Birch A, et al., 2021, Imidazoline ligand BU224 reverses cognitive deficits, reduces microgliosis and enhances synaptic connectivity in a mouse model of Alzheimer’s disease, British Journal of Pharmacology, Vol: 178, Pages: 654-671, ISSN: 0007-1188
Background and PurposeActivation of type‐2 Imidazoline receptors has been shown to exhibit neuroprotective properties including anti‐apoptotic and anti‐inflammatory effects, suggesting a potential therapeutic value in Alzheimer's disease (AD). Here, we explored the effects of the Imidazoline‐2 ligand BU224 in a model of amyloidosis.Experimental approach6‐month‐old female transgenic 5XFAD and wild‐type (WT) mice were treated intraperitoneally with 5 mg.kg‐1 BU224 or vehicle twice a day for 10 days. Behavioural tests were performed for cognitive functions and neuropathological changes were investigated by immunohistochemistry, Western blot, ELISA and qPCR. Effects of BU224 on APP processing, spine density and calcium imaging were analysed in brain organotypic cultures and N2a cells.Key ResultsBU224 treatment attenuated spatial and perirhinal cortex‐dependent recognition memory deficits in 5XFAD mice. Fear conditioning testing revealed that BU224 also improved both associative learning and hippocampal‐ and amygdala‐dependent memory in transgenic but not in WT mice. In the brain, BU224 reduced levels of the microglial marker Iba1 and pro‐inflammatory cytokines IL‐1β and TNFα, and increased the expression of astrocytic marker GFAP in 5XFAD mice. These beneficial effects were not associated with changes in amyloid pathology, neuronal apoptosis, mitochondrial density, oxidative stress or autophagy markers. Interestingly, ex vivo and in vitro studies suggested that BU224 treatment increased the size of dendritic spines and induced a 3‐fold reduction in Aβ‐induced functional changes in NMDA receptors.Conclusions and implicationsOur data indicate that sub‐chronic treatment with BU224 improves memory and reduces inflammation in transgenic AD mice, at stages when animals display severe pathology.
Bengoa-Vergniory N, Velentza-Almpani E, Silva AM, et al., 2021, Tau-proximity ligation assay reveals extensive previously undetected pathology prior to neurofibrillary tangles in preclinical Alzheimer’s disease, Acta Neuropathologica Communications, Vol: 9, ISSN: 2051-5960
BackgroundMultimerization is a key process in prion-like disorders such as Alzheimer’s disease (AD), since it is a requirement for self-templating tau and beta-amyloid amyloidogenesis. AT8-immunohistochemistry for hyperphosphorylated tau is currently used for the diagnosis and staging of tau pathology. Given that tau–tau interactions can occur in the absence of hyperphosphorylation or other post-translational modifications (PTMs), the direct visualization of tau multimerization could uncover early pathological tau multimers.MethodsHere, we used bimolecular fluorescent complementation, rapamycin-dependent FKBP/FRB-tau interaction and transmission electron microscopy to prove the in vitro specificity of tau-proximity ligation assay (tau-PLA). We then analyzed MAPT KO and P301S transgenic mice, and human hippocampus and temporal isocortex of all Braak stages with tau-PLA and compared it with immunohistochemistry for the diagnostic antibody AT8, the early phosphorylation-dependent AT180, and the conformational-dependent antibody MC1. Finally, we performed proteinase-K treatment to infer the content of amyloidogenic beta-sheet fold.ResultsOur novel tau-proximity ligation assay (tau-PLA) directly visualized tau–tau interactions in situ, and exclusively recognized tau multimers but not monomers. It elicited no signal in MAPT KO mouse brains, but extensively labelled P301S transgenic mice and AD brain. Two groups of structures were detected, a previously unreported widespread small-sized diffuse pathology and large, neurofibrillary-like lesions. Tau-PLA-labelled diffuse pathology appeared from the earliest Braak stages, mostly unaccompanied by tangle-like tau-immunohistochemistry, being significantly more sensitive than any small-sized dot-/thread-like pathology labelled by AT180-, AT8- and MC1-immunohistochemistry in most regions quantified at stages 0-II. Tau-PLA-labelled diffuse pathology was extremely sensitive to Proteinase-K, in contrast to large les
Donat C, Yanez Lopez M, Sastre M, et al., 2021, From biomechanics to pathology: predicting axonal injury from patterns of strain after traumatic brain injury., Brain: a journal of neurology, Vol: 144, Pages: 70-91, ISSN: 0006-8950
The relationship between biomechanical forces and neuropathology is key to understanding traumatic brain injury. White matter tracts are damaged by high shear forces during impact, resulting in axonal injury, a key determinant of long-term clinical outcomes. However, the relationship between biomechanical forces and patterns of white matter injuries, associated with persistent diffusion MRI abnormalities, is poorly understood. This limits the ability to predict the severity of head injuries and the design of appropriate protection. Our previously developed human finite element model of head injury predicted the location of post-traumatic neurodegeneration. A similar rat model now allows us to experimentally test whether strain patterns calculated by the model predicts in vivo MRI and histology changes. Using a Controlled Cortical Impact, mild and moderate injuries(1 and 2 mm) were performed. Focal and axonal injuries were quantified withvolumetric and diffusion 9.4T MRI two weeks post injury. Detailed analysis of the corpus callosum was conducted using multi-shell diffusion MRI and histopathology. Microglia and astrocyte density, including process parameters,along with white matter structural integrity and neurofilament expression were determined by quantitative immunohistochemistry. Linear mixed effects regression analyses for strain and strain rate with the employed outcome measures were used to ascertain how well immediate biomechanics could explain MRI and histology changes.The spatial pattern of mechanical strain and strain rate in the injured cortex shows good agreement with the probability maps of focal lesions derived from volumetric MRI. Diffusion metrics showed abnormalities in segments of the corpus callosum predicted to have a high strain, indicating white matter changes. The same segments also exhibited a severity-dependent increase in glia cell density, white matter thinning
Mota BC, Almpani EV, Nikolaou MN, et al., 2020, Investigation of the effect of PGC1A gene therapy at advanced stages of Alzheimer’s disease in an animal model of amyloid pathology, Alzheimer's & Dementia, Vol: 16, ISSN: 1552-5260
Davis N, Mota BC, Stead L, et al., 2020, Ablation of astrocytes affects Aβ degradation, microglia activation and synaptic connectivity in an ex vivo model of Alzheimer’s disease, Alzheimer's & Dementia, Vol: 16, ISSN: 1552-5260
Davis N, Mota B, Stead L, et al., 2020, Pharmacological ablation of astrocytes reduces Aβ degradation and synaptic connectivity in an ex vivo model of Alzheimer’s disease, Publisher: BioMed Central
Katsouri L, Birch A, Renziehausen A, et al., 2020, Ablation of reactive astrocytes exacerbates disease pathology in a model of Alzheimer’s disease, Glia, Vol: 68, Pages: 1017-1030, ISSN: 0894-1491
The role of astrocytes in the progression of Alzheimer’s disease (AD) remains poorly understood. We assessed the consequences of ablating astrocytic proliferation in 9 months old double transgenic APP23/GFAP-TK mice. Treatment of these mice with the antiviral agent ganciclovir conditionally ablates proliferating reactive astrocytes. The loss of proliferating astrocytes resulted in significantly increased levels of monomeric amyloid-β (Aβ) in brain homogenates, associated with reduced enzymatic degradation and clearance mechanisms. In addition, our data revealed exacerbated memory deficits in mice lacking proliferating astrocytes concomitant with decreased levels of synaptic markers and higher expression of pro-inflammatory cytokines. Our data suggest that loss of reactive astrocytes in AD aggravates amyloid pathology and memory loss, possibly via disruption of amyloid clearance and enhanced neuroinflammation.
Velentza-Almpani E, Bengoa-Vergniory N, Silva A, et al., 2020, Understanding the pathophysiological role of early tau aggregates in Alzheimer's disease by their direct visualisation in situ, 121st Meeting of the British-Neuropathological-Society / Developmental Neuropathology Symposium, Publisher: WILEY, Pages: 42-42, ISSN: 0305-1846
Pickering J, Ries M, Solito E, et al., 2019, Administration of annexin-A1 reduces tau phosphorylation in the tau-P301L mouse model, British-Pharmacology-Society Meeting (Pharmacology), Publisher: WILEY, Pages: 3024-3024, ISSN: 0007-1188
Palmer E, Tyacke R, Sastre M, et al., 2019, Alcohol hangover: underlying biochemical, inflammatory and neurochemical mechanisms, Alcohol and Alcoholism, Vol: 54, Pages: 196-203, ISSN: 0735-0414
AIM: To review current alcohol hangover research in animals and humans and evaluate key evidence for contributing biological factors. METHOD: Narrative review with alcohol hangover defined as the state the day after a single episode of heavy drinking, when the alcohol concentration in the blood approaches zero. RESULTS: Many of the human studies of hangover are not well controlled, with subjects consuming different concentrations of alcohol over variable time periods and evaluation not blinded. Also, studies have measured different symptoms and use varying methods of measurement. Animal studies show variations with respect to the route of administration (intragastric or intraperitoneal), the behavioural tests utilised and discrepancy in the timepoint used for hangover onset. Human studies have the advantage over animal models of being able to assess subjective hangover severity and its correlation with specific behaviours and/or biochemical markers. However, animal models provide valuable insight into the neural mechanisms of hangover. Despite such limitations, several hangover models have identified pathological changes which correlate with the hangover state. We review studies examining the contribution of alcohol's metabolites, neurotransmitter changes with particular reference to glutamate, neuroinflammation and ingested congeners to hangover severity. CONCLUSION: Alcohol metabolites, neurotransmitter alterations, inflammatory factors and mitochondrial dysfunction are the most likely factors in hangover pathology. Future research should aim to investigate the relationship between these factors and their causal role.
Goldfinger M, Tilley B, Sastre M, et al., 2019, A tale of two tauopathies: a comparison of vasculature changes in ARTAG and chronic traumatic encephalopathy, 120th Meeting of the British-Neuropathological-Society (BNS) / Developmental Neuropathology Symposium, Publisher: WILEY, Pages: 13-13, ISSN: 0305-1846
Goldfinger MH, Tilley B, Mediratta S, et al., 2019, Chronic traumatic encephalopathy: The role of gliovascular pathology, 19th International Congress of Neuropathology, Publisher: WILEY, Pages: 10-10, ISSN: 1015-6305
Zhang N, Parr C, Birch A, et al., 2018, The amyloid precursor protein binds to β-catenin and modulates its cellular distribution, Neuroscience Letters, Vol: 685, Pages: 190-195, ISSN: 0304-3940
Accumulating evidence has shown that the processing of the amyloid precursor protein (APP) and the formation of amyloid-β are associated with the canonical Wnt/ β-catenin signalling pathway. It was recently published that the drosophila homologue of APP is a conserved modulator of Wnt PCP signalling, suggesting a potential regulation of this pathway by APP. The aim of this study was to investigate the potential interaction of APP with the canonical Wnt pathway. APP overexpression in N2a cells led to alterations in the subcellular distribution of β-catenin by physically binding to it, preventing its translocation to the nucleus and precluding the transcription of Wnt target genes. In addition, studies in APP transgenic mice and human Alzheimer’s disease (AD) brain tissue showed the cellular co-localization of APP and β-catenin and binding of both proteins, suggesting the formation physical complexes of APP and β-catenin, yet not present in healthy controls. Furthermore, a reduction in the levels of nuclear β-catenin was detected in AD brains compared to controls as well as a decrease in the expression of the inactive phosphorylated Glycogen synthase kinase 3 (GSK3) isoform. Therefore, these findings indicate a reciprocal regulation of Wnt/ β-catenin signalling pathway and APP processing involving a physical interaction between APP and β-catenin.
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
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