publications
by theme
publications by theme
Inflammation in dementia with Lewy bodies
Amin J, Erskine D, Donaghy PC, Surendranathan A, Swann P, Kunicki AP, Boche D, Holmes C, McKeith IG, O'Brien JT, Teeling JL and Thomas AJ
Inflammation in dementia with Lewy bodies
Amin J, Erskine D, Donaghy PC, Surendranathan A, Swann P, Kunicki AP, Boche D, Holmes C, McKeith IG, O'Brien JT, Teeling JL and Thomas AJ
Dementia with Lewy bodies (DLB) is the second most common neurodegenerative cause of dementia, behind Alzheimer's disease (AD). The profile of inflammation in AD has been extensively researched in recent years, with evidence that chronic peripheral inflammation in midlife increases the risk of late-onset AD, and data supporting inflammation being associated with disease progression. In contrast, our understanding of the role of inflammation in DLB is less developed. Most research to date has examined inflammation in related disorders, such as Parkinson's disease, but there is now a growing range of literature examining inflammation in DLB itself. We present a review of the literature in this field, exploring a range of research methodologies including those quantifying markers of inflammation in cerebrospinal fluid, peripheral blood, post-mortem brain tissue, and using neuroimaging and preclinical data. Our review reveals evidence from PET imaging and peripheral blood analysis to support an increase in cerebral and peripheral inflammation in mild or prodromal DLB, that dissipates with disease progression. We present evidence from post-mortem brain tissue and pre-clinical studies that indicate α-synuclein directly promotes inflammation, but that also support the presence of AD co-pathology as an important factor in the profile of neuroinflammation in DLB. We propose that specific markers of inflammation may play a sentinel role in the mild stage of the disease, particularly when combined with AD pathology. We advocate further examination of the profile of inflammation in DLB through robust longitudinal studies, to enhance our understanding of the pathogenesis of the disease. The goal should be to utilise future results to develop a composite biomarker to aid diagnosis of DLB, and to potentially identify novel therapeutic targets.
Repeated short-term exposure to diesel exhaust reduces honey bee colony fitness
Reitmayer CM, Girling RD, Jackson CW and Newman TA
Repeated short-term exposure to diesel exhaust reduces honey bee colony fitness
Reitmayer CM, Girling RD, Jackson CW and Newman TA
Production of insect-pollinated crops is often reliant on honey bee (Apis mellifera) pollination services. Colonies can be managed and moved to meet the demands of modern intensified monoculture farming systems. Increased colony mortalities have been observed, which are thought be caused by interacting factors including exposure to pesticides, parasites, viruses, agricultural intensification, and changes in global and regional climate. However, whilst common tropospheric air pollutants (e.g. NO, particulate matter etc) are known to cause a range of negative effects on human health, there is little evidence of their impact on the health of A. mellifera. This study investigates the effects of exposure to diesel exhaust on A. mellifera, both at the level of individual foragers and on the whole colony. We exposed a series of colonies to diesel exhaust fumes for 2 h a day over the course of three weeks and contrasted their performance to a series of paired control colonies located at the same field site. We investigated markers of neuronal health in the brains of individual foragers and measured the prevalence of common viruses. Electronic counters monitored daily colony activity patterns and pollen samples from returning foragers were analysed to investigate plant species richness and diversity. The amounts of honey, brood and pollen in each colony were measured regularly. We demonstrated an upregulation of the synapse protein Neurexin 1 in forager brains repeatedly exposed to diesel exhaust. Furthermore, we found that colonies exposed to diesel exhaust lost colony weight after the exposure period until the end of the summer season, whereas control colonies gained weight towards the end of the season. Further investigations are required, but we hypothesise that such effects on both individual foragers and whole colony fitness parameters could ultimately contribute to winter losses of honey bee colonies, particularly in the presence of additional stressors.
Decreased CSF clearance and increased brain amyloid in Alzheimer's disease
Li Y, Rusinek H, Butler T, Glodzik L, Pirraglia E, Babich J, Mozley PD, Nehmeh S, Pahlajani S, Wang X, Tanzi EB, Zhou L, Strauss S, Carare RO, Theise N, Okamura N and de Leon MJ
Decreased CSF clearance and increased brain amyloid in Alzheimer's disease
Li Y, Rusinek H, Butler T, Glodzik L, Pirraglia E, Babich J, Mozley PD, Nehmeh S, Pahlajani S, Wang X, Tanzi EB, Zhou L, Strauss S, Carare RO, Theise N, Okamura N and de Leon MJ
In sporadic Alzheimer's disease (AD), brain amyloid-beta (Aβ) deposition is believed to be a consequence of impaired Aβ clearance, but this relationship is not well established in living humans. CSF clearance, a major feature of brain glymphatic clearance (BGC), has been shown to be abnormal in AD murine models. MRI phase contrast and intrathecally delivered contrast studies have reported reduced CSF flow in AD. Using PET and tau tracer F-THK5117, we previously reported that the ventricular CSF clearance of the PET tracer was reduced in AD and associated with elevated brain Aβ levels.
Various Options for Scrotal Reconstruction: A Prospective Observational Study
Maurya R, Mir MA and Mahajan S
Various Options for Scrotal Reconstruction: A Prospective Observational Study
Maurya R, Mir MA and Mahajan S
Background Scrotal defects in developing countries are common challenges for the reconstructive surgeon and hence this work has been done with the aim to compare the outcome, advantages and disadvantages of different modalities of scrotal reconstruction. Methods The prospective observational hospital-based study of reconstruction of scrotal defects following trauma and Fournier's gangrene was done over a period of three years. Scrotal defect reconstruction was done in 35 patients by scrotal advancement flap, split thickness skin grafting, medial thigh flap, anterolateral thigh flap and groin flap keeping in mind the various indication of different modalities. The reconstructed scrotums were observed for flap survival and skin graft intake for seven to 10 days in the hospital and then were followed for three months in a follow-up clinic. Results and observations The mean age of our patients was 48.57±5.01 years. Most of the soft tissue defects of the scrotum were post-traumatic (83%). Scrotal reconstruction was done often by flaps and more frequently used flap for reconstruction of scrotum was scrotal advancement flap. All flaps and grafts survived well. Mean hospitalization time was highest for groin flap cover whereas mean operative time was highest for anterolateral thigh flap cover. Conclusion Every case of scrotal defect needs an individual approach for scrotal reconstruction depending upon patient age, general condition of the patient, wound status, and the patient's requirement.
Macrophages in the cochlea; an immunological link between risk factors and progressive hearing loss
Hough K, Verschuur CA, Cunningham C and Newman TA
Macrophages in the cochlea; an immunological link between risk factors and progressive hearing loss
Hough K, Verschuur CA, Cunningham C and Newman TA
Macrophages are abundant in the cochlea; however, their role in hearing loss is not well understood. Insults to the cochlea, such as noise or insertion of a cochlear implant, cause an inflammatory response, which includes activation of tissue-resident macrophages. Activation is characterized by changes in macrophage morphology, mediator expression, and distribution. Evidence from other organs shows activated macrophages can become primed, whereby subsequent insults cause an elevated inflammatory response. Primed macrophages in brain pathologies respond to circulating inflammatory mediators by disproportionate synthesis of inflammatory mediators. This signaling occurs behind an intact blood-brain barrier, similar to the blood-labyrinth barrier in the cochlea. Local tissue damage can occur as the result of mediator release by activated macrophages. Damage is typically localized; however, if it is to structures with limited ability to repair, such as neurons or hair cells within the cochlea, it is feasible that this contributes to the progressive loss of function seen in hearing loss. We propose that macrophages in the cochlea link risk factors and hearing loss. Injury to the cochlea causes local macrophage activation that typically resolves. However, in susceptible individuals, some macrophages enter a primed state. Once primed, these macrophages can be further activated, as a consequence of circulating inflammatory molecules associated with common co-morbidities. Hypothetically, this would lead to further cochlear damage and loss of hearing. We review the evidence for the role of tissue-resident macrophages in the cochlea and propose that cochlear macrophages contribute to the trajectory of hearing loss and warrant further study.
Immunisation with UB-312 in the Thy1SNCA mouse prevents motor performance deficits and oligomeric α-synuclein accumulation in the brain and gut
Nimmo JT, Smith H, Wang CY, Teeling JL, Nicoll JAR, Verma A, Dodart JC, Liu Z, Lin F and Carare RO
Immunisation with UB-312 in the Thy1SNCA mouse prevents motor performance deficits and oligomeric α-synuclein accumulation in the brain and gut
Nimmo JT, Smith H, Wang CY, Teeling JL, Nicoll JAR, Verma A, Dodart JC, Liu Z, Lin F and Carare RO
Alpha synuclein has a key role in the pathogenesis of Parkinson's disease (PD), Dementia with Lewy Bodies (LBD) and Multiple System Atrophy (MSA). Immunotherapies aiming at neutralising toxic αSyn species are being investigated in the clinic as potential disease modifying therapies for PD and other synucleinopathies. In this study, the effects of active immunisation against αSyn with the UB-312 vaccine were investigated in the Thy1SNCA/15 mouse model of PD. Young transgenic and wild-type mice received an immunisation regimen over a period of 6 weeks, then observed for an additional 9 weeks. Behavioural assessment was conducted before immunisation and at 15 weeks after the first dose. UB-312 immunisation prevented the development of motor impairment in the wire test and challenging beam test, which was associated with reduced levels of αSyn oligomers in the cerebral cortex, hippocampus and striatum of Thy1SNCA/15 mice. UB-312 immunotherapy resulted in a significant reduction of theαSyn load in the colon, accompanied by a reduction in enteric glial cell reactivity in the colonic ganglia. Our results demonstrate that immunisation with UB-312 prevents functional deficits and both central and peripheral pathology in Thy1SNCA/15 mice.
Physiology and Clinical Relevance of Enlarged Perivascular Spaces in the Aging Brain
Bown CW, Carare RO, Schrag MS and Jefferson AL
Physiology and Clinical Relevance of Enlarged Perivascular Spaces in the Aging Brain
Bown CW, Carare RO, Schrag MS and Jefferson AL
Perivascular spaces (PVS) are fluid-filled compartments that are part of the cerebral blood vessel wall and represent the conduit for fluid transport in and out of the brain. PVS are considered pathologic when sufficiently enlarged to be visible on MRI. Recent studies have demonstrated that enlarged PVS (ePVS) may have clinical consequences related to cognition. Emerging literature points to arterial stiffening and abnormal protein aggregation in vessel walls as 2 possible mechanisms that drive ePVS formation. We describe the clinical consequences, anatomy, fluid dynamics, physiology, risk factors, and in vivo quantification methods of ePVS. Given competing views of PVS physiology, we detail the 2 most prominent theoretical views and review ePVS associations with other common small vessel disease markers. Because ePVS are a marker of small vessel disease and ePVS burden is higher in Alzheimer disease, a comprehensive understanding about ePVS is essential in developing prevention and treatment strategies.
Multi-Excitation Raman Spectroscopy for Label-Free, Strain-Level Characterization of Bacterial Pathogens in Artificial Sputum Media
Lister AP, Highmore CJ, Hanrahan N, Read J, Munro APS, Tan S, Allan RN, Faust SN, Webb JS and Mahajan S
Multi-Excitation Raman Spectroscopy for Label-Free, Strain-Level Characterization of Bacterial Pathogens in Artificial Sputum Media
Lister AP, Highmore CJ, Hanrahan N, Read J, Munro APS, Tan S, Allan RN, Faust SN, Webb JS and Mahajan S
The current methods for diagnosis of acute and chronic infections are complex and skill-intensive. For complex clinical biofilm infections, it can take days from collecting and processing a patient's sample to achieving a result. These aspects place a significant burden on healthcare providers, delay treatment, and can lead to adverse patient outcomes. We report the development and application of a novel multi-excitation Raman spectroscopy-based methodology for the label-free and non-invasive detection of microbial pathogens that can be used with unprocessed clinical samples directly and provide rapid data to inform diagnosis by a medical professional. The method relies on the differential excitation of non-resonant and resonant molecular components in bacterial cells to enhance the molecular finger-printing capability to obtain strain-level distinction in bacterial species. Here, we use this strategy to detect and characterize the respiratory pathogens and as typical infectious agents associated with cystic fibrosis. Planktonic specimens were analyzed both in isolation and in artificial sputum media. The resonance Raman components, excited at different wavelengths, were characterized as carotenoids and porphyrins. By combining the more informative multi-excitation Raman spectra with multivariate analysis (support vector machine) the accuracy was found to be 99.75% for both species (across all strains), including 100% accuracy for drug-sensitive and drug-resistant . The results demonstrate that our methodology based on multi-excitation Raman spectroscopy can underpin the development of a powerful platform for the rapid and reagentless detection of clinical pathogens to support diagnosis by a medical expert, in this case relevant to cystic fibrosis. Such a platform could provide translatable diagnostic solutions in a variety of disease areas and also be utilized for the rapid detection of anti-microbial resistance.
TUBE Project: Transport-Derived Ultrafines and the Brain Effects
Martikainen MV, Aakko-Saksa P, van den Broek L, Cassee FR, Carare RO, Chew S, Dinnyes A, Giugno R, Kanninen KM, Malm T, Muala A, Nedergaard M, Oudin A, Oyola P, Pfeiffer TV, Rönkkö T, Saarikoski S, Sandström T, Schins RPF, Topinka J, Yang M, Zeng X, Westerink RHS and Jalava PI
TUBE Project: Transport-Derived Ultrafines and the Brain Effects
Martikainen MV, Aakko-Saksa P, van den Broek L, Cassee FR, Carare RO, Chew S, Dinnyes A, Giugno R, Kanninen KM, Malm T, Muala A, Nedergaard M, Oudin A, Oyola P, Pfeiffer TV, Rönkkö T, Saarikoski S, Sandström T, Schins RPF, Topinka J, Yang M, Zeng X, Westerink RHS and Jalava PI
The adverse effects of air pollutants on the respiratory and cardiovascular systems are unquestionable. However, in recent years, indications of effects beyond these organ systems have become more evident. Traffic-related air pollution has been linked with neurological diseases, exacerbated cognitive dysfunction, and Alzheimer's disease. However, the exact air pollutant compositions and exposure scenarios leading to these adverse health effects are not known. Although several components of air pollution may be at play, recent experimental studies point to a key role of ultrafine particles (UFPs). While the importance of UFPs has been recognized, almost nothing is known about the smallest fraction of UFPs, and only >23 nm emissions are regulated in the EU. Moreover, the role of the semivolatile fraction of the emissions has been neglected. The Transport-Derived Ultrafines and the Brain Effects (TUBE) project will increase knowledge on harmful ultrafine air pollutants, as well as semivolatile compounds related to adverse health effects. By including all the major current combustion and emission control technologies, the TUBE project aims to provide new information on the adverse health effects of current traffic, as well as information for decision makers to develop more effective emission legislation. Most importantly, the TUBE project will include adverse health effects beyond the respiratory system; TUBE will assess how air pollution affects the brain and how air pollution particles might be removed from the brain. The purpose of this report is to describe the TUBE project, its background, and its goals.
Antibiotic-Loaded Polymersomes for Clearance of Intracellular
Porges E, Jenner D, Taylor AW, Harrison JSP, De Grazia A, Hailes AR, Wright KM, Whelan AO, Norville IH, Prior JL, Mahajan S, Rowland CA, Newman TA and Evans ND
Antibiotic-Loaded Polymersomes for Clearance of Intracellular
Porges E, Jenner D, Taylor AW, Harrison JSP, De Grazia A, Hailes AR, Wright KM, Whelan AO, Norville IH, Prior JL, Mahajan S, Rowland CA, Newman TA and Evans ND
Melioidosis caused by the facultative intracellular pathogen is difficult to treat due to poor intracellular bioavailability of antibiotics and antibiotic resistance. In the absence of novel compounds, polymersome (PM) encapsulation may increase the efficacy of existing antibiotics and reduce antibiotic resistance by promoting targeted, infection-specific intracellular uptake. In this study, we developed PMs composed of widely available poly(ethylene oxide)-polycaprolactone block copolymers and demonstrated their delivery to intracellular infection using multispectral imaging flow cytometry (IFC) and coherent anti-Stokes Raman scattering microscopy. Antibiotics were tightly sequestered in PMs and did not inhibit the growth of free-living . However, on uptake of antibiotic-loaded PMs by infected macrophages, IFC demonstrated PM colocalization with intracellular and a significant inhibition of their growth. We conclude that PMs are a viable approach for the targeted antibiotic treatment of persistent intracellular infection.
Suppression of tau-induced phenotypes by vitamin E demonstrates the dissociation of oxidative stress and phosphorylation in mechanisms of tau toxicity
Cowan CM, Sealey MA and Mudher A
Suppression of tau-induced phenotypes by vitamin E demonstrates the dissociation of oxidative stress and phosphorylation in mechanisms of tau toxicity
Cowan CM, Sealey MA and Mudher A
Various lines of evidence implicate oxidative stress in the pathogenic mechanism(s) underpinning tauopathies. Consequently, antioxidant therapies have been considered in clinical practice for the treatment of tauopathies such as Alzheimer's disease (AD), but with mixed results. We and others have previously reported increased protein oxidation upon expression of both human 0N3R (hTau ) and 0N4R (hTau ) tau in vivo. Building on these studies, we demonstrate here the suppression of hTau associated phenotypes in Drosophila melanogaster after treatment with vitamin C or vitamin E. Curiously the rescue of phenotype was seen without alteration in total tau level or alteration in phosphorylation at a number of disease-associated sites. Moreover, treatment with paraquat, a pro-oxidant drug, did not exacerbate the hTau phenotypes. This result following paraquat treatment is reminiscent of our previous findings with hTau which also causes greater oxidative stress when compared to hTau but has a milder phenotype. Collectively our data imply that the role of oxidative stress in tau-mediated toxicity is not straight forward and there may be isoform-specific effects as well as contribution of other factors. This may explain the ambiguous effects of anti-oxidant treatments on clinical outcome in dementia patients.
Superresolved polarization-enhanced second-harmonic generation for direct imaging of nanoscale changes in collagen architecture
Johnson PB, Karvounis A, Singh HJ, Brereton CJ, Bourdakos KN, Lunn K, Roberts JJW, Davies DE, Muskens OL, Jones MG and Mahajan S
Superresolved polarization-enhanced second-harmonic generation for direct imaging of nanoscale changes in collagen architecture
Johnson PB, Karvounis A, Singh HJ, Brereton CJ, Bourdakos KN, Lunn K, Roberts JJW, Davies DE, Muskens OL, Jones MG and Mahajan S
Superresolution (SR) optical microscopy has allowed the investigation of many biological structures below the diffraction limit; however, most of the techniques are hampered by the need for fluorescent labels. Nonlinear label-free techniques such as second-harmonic generation (SHG) provide structurally specific contrast without the addition of exogenous labels, allowing observation of unperturbed biological systems. We use the photonic nanojet (PNJ) phenomena to achieve SR-SHG. A resolution of with respect to the fundamental wavelength, that is, a -fold improvement over conventional or diffraction-limited SHG under the same imaging conditions is achieved. Crucially we find that the polarization properties of excitation are maintained in a PNJ. This is observed in experiment and simulations. This may have widespread implications to increase sensitivity by detection of polarization-resolved SHG by observing anisotropy in signals. These new, to the best of our knowledge, findings allowed us to visualize biological SHG-active structures such as collagen at an unprecedented and previously unresolvable spatial scale. Moreover, we demonstrate that the use of an array of self-assembled high-index spheres overcomes the issue of a limited field of view for such a method, allowing PNJ-assisted SR-SHG to be used over a large area. Dysregulation of collagen at the nanoscale occurs in many diseases and is an underlying cause in diseases such as lung fibrosis. Here we demonstrate that pSR-SHG allows unprecedented observation of changes at the nanoscale that are invisible by conventional diffraction-limited SHG imaging. The ability to nondestructively image SHG-active biological structures without labels at the nanoscale with a relatively simple optical method heralds the promise of a new tool to understand biological phenomena and drive drug discovery.
Inflammation at the Tissue-Electrode Interface in a Case of Rapid Deterioration in Hearing Performance Leading to Explant After Cochlear Implantation
Hough K, Sanderson A, Grasmeder M, Mitchell T, Verschuur CA and Newman TA
Inflammation at the Tissue-Electrode Interface in a Case of Rapid Deterioration in Hearing Performance Leading to Explant After Cochlear Implantation
Hough K, Sanderson A, Grasmeder M, Mitchell T, Verschuur CA and Newman TA
The reasons for soft failure after cochlear implantation require investigation. This study proposes a method to study and characterize the tissue response to the array in a case of soft failure in a person undergoing reimplantation.
Progress in developing rodent models of age-related macular degeneration (AMD)
Soundara Pandi SP, Ratnayaka JA, Lotery AJ and Teeling JL
Progress in developing rodent models of age-related macular degeneration (AMD)
Soundara Pandi SP, Ratnayaka JA, Lotery AJ and Teeling JL
Age-related macular degeneration (AMD) is the leading cause of irreversible central vision loss, typically affecting individuals from mid-life onwards. Its multifactorial aetiology and the lack of any effective treatments has spurred the development of animal models as research and drug discovery tools. Several rodent models have been developed which recapitulate key features of AMD and provide insights into its underlying pathology. These have contributed to making significant progress in understanding the disease and the identification of novel therapeutic targets. However, a major caveat with existing models is that they do not demonstrate the full disease spectrum. In this review, we outline advances in rodent AMD models from the last decade. These models feature various hallmarks associated with AMD, including oxidative stress, hypoxia, immune dysregulation, genetic mutations and environmental risk factors. The review summarises the methods by which each model was created, its pathological characteristics as well as its relation to the disease in humans.
Oligomeric Aβ Induces an AMD-Like Phenotype and Accumulates in Lysosomes to Impair RPE Function
Lynn SA, Johnston DA, Scott JA, Munday R, Desai RS, Keeling E, Weaterton R, Simpson A, Davis D, Freeman T, Chatelet DS, Page A, Cree AJ, Lee H, Newman TA, Lotery AJ and Ratnayaka JA
Oligomeric Aβ Induces an AMD-Like Phenotype and Accumulates in Lysosomes to Impair RPE Function
Lynn SA, Johnston DA, Scott JA, Munday R, Desai RS, Keeling E, Weaterton R, Simpson A, Davis D, Freeman T, Chatelet DS, Page A, Cree AJ, Lee H, Newman TA, Lotery AJ and Ratnayaka JA
Alzheimer's disease-associated amyloid beta (Aβ) proteins accumulate in the outer retina with increasing age and in eyes of age-related macular degeneration (AMD) patients. To study Aβ-induced retinopathy, wild-type mice were injected with nanomolar human oligomeric Aβ, which recapitulate the Aβ burden reported in human donor eyes. In vitro studies investigated the cellular effects of Aβ in endothelial and retinal pigment epithelial (RPE) cells. Results show subretinal Aβ-induced focal AMD-like pathology within 2 weeks. Aβ exposure caused endothelial cell migration, and morphological and barrier alterations to the RPE. Aβ co-localized to late-endocytic compartments of RPE cells, which persisted despite attempts to clear it through upregulation of lysosomal cathepsin B, revealing a novel mechanism of lysosomal impairment in retinal degeneration. The rapid upregulation of cathepsin B was out of step with the prolonged accumulation of Aβ within lysosomes, and contrasted with enzymatic responses to internalized photoreceptor outer segments (POS). Furthermore, RPE cells exposed to Aβ were identified as deficient in cargo-carrying lysosomes at time points that are critical to POS degradation. These findings imply that Aβ accumulation within late-endocytic compartments, as well as lysosomal deficiency, impairs RPE function over time, contributing to visual defects seen in aging and AMD eyes.
An evaluation of Drosophila as a model system for studying tauopathies such as Alzheimer's disease
Sivanantharajah L, Mudher A and Shepherd D
An evaluation of Drosophila as a model system for studying tauopathies such as Alzheimer's disease
Sivanantharajah L, Mudher A and Shepherd D
Work spanning almost two decades using the fruit fly, Drosophila melanogaster, to study tau-mediated neurodegeneration has provided valuable and novel insights into the causes and mechanisms of tau-mediated toxicity and dysfunction in tauopathies such as Alzheimer's disease (AD). The fly has proven to be an excellent model for human diseases because of its cost efficiency, and the availability of powerful genetic tools for use in a comparatively less-complicated, but evolutionarily conserved, in vivo system. In this review, we provide a critical evaluation of the insights provided by fly models, highlighting both the advantages and limitations of the system. The fly has contributed to a greater understanding of the causes of tau abnormalities, the role of these abnormalities in mediating toxicity and/or dysfunction, and the nature of causative species mediating tau-toxicity. However, it is not possible to perfectly model all aspects of human degenerative diseases. What sets the fly apart from other animal models is its genetic tractability, which makes it highly amenable to overcoming experimental limitations. The explosion of genetic technology since the first fly disease models were established has translated into fly lines that allow for greater temporal control in restricting tau expression to single neuron types, and lines that can label and monitor the function of subcellular structures and components; thus, fly models offer an unprecedented view of the neurodegenerative process. Emerging genetic technology means that the fly provides an ever-evolving experimental platform for studying disease.
Pyroglutamate and Isoaspartate modified Amyloid-Beta in ageing and Alzheimer's disease
Moro ML, Phillips AS, Gaimster K, Paul C, Mudher A, Nicoll JAR and Boche D
Pyroglutamate and Isoaspartate modified Amyloid-Beta in ageing and Alzheimer's disease
Moro ML, Phillips AS, Gaimster K, Paul C, Mudher A, Nicoll JAR and Boche D
Alzheimer's disease (AD) is the most common cause of dementia among older adults. Accumulation of amyloid-β (Aβ) in the brain is considered central in AD pathogenesis and its understanding crucial for developing new diagnostic and therapeutic approaches. Recent literature suggests that ageing may induce post translational modifications in Aβ, in the form of spontaneous amino acid modifications, which enhance its pathogenic properties, contributing to its aggregation.In this study, we have investigated whether the isoaspartate (IsoD-Aβ) and pyroglutamate (pE3-Aβ) modified forms of Aβ are significantly associated with AD pathology or represent markers of ageing. Cerebral neocortex of 27 AD cases, 32 old controls (OC) and 11 young controls (YC) was immunostained for pE3-Aβ and IsoD-Aβ, quantified as protein load and correlated with other Aβ forms and p-TAU. IsoD-Aβ and pE3-Aβ were detected at low levels in non-demented controls, and significantly increased in AD (p ≤ 0.001), with a characteristic deposition of IsoD-Aβ in blood vessel walls and pE3-Aβ within neurons. Both AD and OC showed positive associations between IsoD-Aβ and Aβ (p = 0.003 in AD and p = 0.001 in OC) and between IsoD-Aβ and pE3-Aβ (p = 0.001 in AD and OC). This last association was the only significant pE3-Aβ correlation identified in AD, whereas in the control cohorts pE3-Aβ also correlated with Aβ and AβPP (p = 0.001 in OC and p = 0.010 in YC).Our analyses suggest that IsoD-Aβ accumulation starts with ageing; whereas pE3-Aβ deposition is more closely linked to AD. Our findings support the importance of age-related modifications of Aβ in AD pathogenesis.
Research priorities for neuroimmunology: identifying the key research questions to be addressed by 2030
MacKenzie G, Subramaniam S, Caldwell LJ, Fitzgerald D, Harrison NA, Hong S, Irani SR, Khandaker GM, Liston A, Miron VE, Mondelli V, Morgan BP, Pariante C, Shah DK, Taams LS, Teeling JL and Upthegrove R
Research priorities for neuroimmunology: identifying the key research questions to be addressed by 2030
MacKenzie G, Subramaniam S, Caldwell LJ, Fitzgerald D, Harrison NA, Hong S, Irani SR, Khandaker GM, Liston A, Miron VE, Mondelli V, Morgan BP, Pariante C, Shah DK, Taams LS, Teeling JL and Upthegrove R
Neuroimmunology in the broadest sense is the study of interactions between the nervous and the immune systems. These interactions play important roles in health from supporting neural development, homeostasis and plasticity to modifying behaviour. Neuroimmunology is increasingly recognised as a field with the potential to deliver a significant positive impact on human health and treatment for neurological and psychiatric disorders. Yet, translation to the clinic is hindered by fundamental knowledge gaps on the underlying mechanisms of action or the optimal timing of an intervention, and a lack of appropriate tools to visualise and modulate both systems. Here we propose ten key disease-agnostic research questions that, if addressed, could lead to significant progress within neuroimmunology in the short to medium term. We also discuss four cross-cutting themes to be considered when addressing each question: i) bi-directionality of neuroimmune interactions; ii) the biological context in which the questions are addressed (e.g. health vs disease vs across the lifespan); iii) tools and technologies required to fully answer the questions; and iv) translation into the clinic. We acknowledge that these ten questions cannot represent the full breadth of gaps in our understanding; rather they focus on areas which, if addressed, may have the most broad and immediate impacts. By defining these neuroimmunology priorities, we hope to unite existing and future research teams, who can make meaningful progress through a collaborative and cross-disciplinary effort.
Conformational fingerprinting of tau variants and strains by Raman spectroscopy
Devitt G, Crisford A, Rice W, Weismiller HA, Fan Z, Commins C, Hyman BT, Margittai M, Mahajan S and Mudher A
Conformational fingerprinting of tau variants and strains by Raman spectroscopy
Devitt G, Crisford A, Rice W, Weismiller HA, Fan Z, Commins C, Hyman BT, Margittai M, Mahajan S and Mudher A
Tauopathies are a group of disorders in which the deposition of abnormally folded tau protein accompanies neurodegeneration. The development of methods for detection and classification of pathological changes in protein conformation are desirable for understanding the factors that influence the structural polymorphism of aggregates in tauopathies. We have previously demonstrated the utility of Raman spectroscopy for the characterization and discrimination of different protein aggregates, including tau, based on their unique conformational signatures. Building on this, in the present study, we assess the utility of Raman spectroscopy for characterizing and distinguishing different conformers of the same protein which in the case of tau are unique tau strains generated . We now investigate the impact of aggregation environment, cofactors, post-translational modification and primary sequence on the Raman fingerprint of tau fibrils. Using quantitative conformational fingerprinting and multivariate statistical analysis, we found that the aggregation of tau in different buffer conditions resulted in the formation of distinct fibril strains. Unique spectral markers were identified for tau fibrils generated using heparin or RNA cofactors, as well as for phosphorylated tau. We also determined that the primary sequence of the tau monomer influenced the conformational signature of the resulting tau fibril, including 2N4R, 0N3R, K18 and P301S tau variants. These results highlight the conformational polymorphism of tau fibrils, which is reflected in the wide range of associated neurological disorders. Furthermore, the analyses presented in this study provide a benchmark for the Raman spectroscopic characterization of tau strains, which may shed light on how the aggregation environment, cofactors and post-translational modifications influence tau conformation in future studies.
Insulin-Mediated Changes in Tau Hyperphosphorylation and Autophagy in a Model of Tauopathy and Neuroblastoma Cells
Chatterjee S, Ambegaokar SS, Jackson GR and Mudher A
Insulin-Mediated Changes in Tau Hyperphosphorylation and Autophagy in a Model of Tauopathy and Neuroblastoma Cells
Chatterjee S, Ambegaokar SS, Jackson GR and Mudher A
Almost 50 million people in the world are affected by dementia; the most prevalent form of which is Alzheimer's disease (AD). Although aging is considered to be the main risk factor for AD, growing evidence from epidemiological studies suggests that type 2 diabetes mellitus (T2DM) increases the risk of dementia including AD. Defective brain insulin signaling has been suggested as an early event in AD and other tauopathies but the mechanisms that link these diseases are largely unknown. Tau hyperphosphorylation is a hallmark of neurofibrillary pathology and insulin resistance increases the number of neuritic plaques particularly in AD. Utilizing a combination of our models of tauopathy (expressing the 2N4R-Tau) and neuroblastoma cells, we have attempted to decipher the pathways downstream of the insulin signaling cascade that lead to tau hyperphosphorylation, aggregation and autophagic defects. Using cell-based, genetic, and biochemical approaches we have demonstrated that tau phosphorylation at AT8 and PHF1 residues is enhanced in an insulin-resistant environment. We also show that insulin-induced changes in total and phospho-tau are mediated by the crosstalk of AKT, glycogen synthase kinase-3β, and extracellular regulating kinase located downstream of the insulin receptor pathway. Finally, we demonstrate a significant change in the levels of the key proteins in the mammalian target of rapamycin/autophagy pathway, implying an increased impairment of aggregated protein clearance in our transgenic models and cultured neuroblastoma cells.
The Brain-Nose Interface: A Potential Cerebrospinal Fluid Clearance Site in Humans
Mehta NH, Sherbansky J, Kamer AR, Carare RO, Butler T, Rusinek H, Chiang GC, Li Y, Strauss S, Saint-Louis LA, Theise ND, Suss RA, Blennow K, Kaplitt M and de Leon MJ
The Brain-Nose Interface: A Potential Cerebrospinal Fluid Clearance Site in Humans
Mehta NH, Sherbansky J, Kamer AR, Carare RO, Butler T, Rusinek H, Chiang GC, Li Y, Strauss S, Saint-Louis LA, Theise ND, Suss RA, Blennow K, Kaplitt M and de Leon MJ
The human brain functions at the center of a network of systems aimed at providing a structural and immunological layer of protection. The cerebrospinal fluid (CSF) maintains a physiological homeostasis that is of paramount importance to proper neurological activity. CSF is largely produced in the choroid plexus where it is continuous with the brain extracellular fluid and circulates through the ventricles. CSF movement through the central nervous system has been extensively explored. Across numerous animal species, the involvement of various drainage pathways in CSF, including arachnoid granulations, cranial nerves, perivascular pathways, and meningeal lymphatics, has been studied. Among these, there is a proposed CSF clearance route spanning the olfactory nerve and exiting the brain at the cribriform plate and entering lymphatics. While this pathway has been demonstrated in multiple animal species, evidence of a similar CSF egress mechanism involving the nasal cavity in humans remains poorly consolidated. This review will synthesize contemporary evidence surrounding CSF clearance at the nose-brain interface, examining across species this anatomical pathway, and its possible significance to human neurodegenerative disease. Our discussion of a bidirectional nasal pathway includes examination of the immune surveillance in the olfactory region protecting the brain. Overall, we expect that an expanded discussion of the brain-nose pathway and interactions with the environment will contribute to an improved understanding of neurodegenerative and infectious diseases, and potentially to novel prevention and treatment considerations.
Impaired Glymphatic Function and Pulsation Alterations in a Mouse Model of Vascular Cognitive Impairment
Li M, Kitamura A, Beverley J, Koudelka J, Duncombe J, Lennen R, Jansen MA, Marshall I, Platt B, Wiegand UK, Carare RO, Kalaria RN, Iliff JJ and Horsburgh K
Impaired Glymphatic Function and Pulsation Alterations in a Mouse Model of Vascular Cognitive Impairment
Li M, Kitamura A, Beverley J, Koudelka J, Duncombe J, Lennen R, Jansen MA, Marshall I, Platt B, Wiegand UK, Carare RO, Kalaria RN, Iliff JJ and Horsburgh K
Large vessel disease and carotid stenosis are key mechanisms contributing to vascular cognitive impairment (VCI) and dementia. Our previous work, and that of others, using rodent models, demonstrated that bilateral common carotid stenosis (BCAS) leads to cognitive impairment via gradual deterioration of the neuro-glial-vascular unit and accumulation of amyloid-β (Aβ) protein. Since brain-wide drainage pathways (glymphatic) for waste clearance, including Aβ removal, have been implicated in the pathophysiology of VCI via glial mechanisms, we hypothesized that glymphatic function would be impaired in a BCAS model and exacerbated in the presence of Aβ. Male wild-type and Tg-SwDI (model of microvascular amyloid) mice were subjected to BCAS or sham surgery which led to a reduction in cerebral perfusion and impaired spatial learning acquisition and cognitive flexibility. After 3 months survival, glymphatic function was evaluated by cerebrospinal fluid (CSF) fluorescent tracer influx. We demonstrated that BCAS caused a marked regional reduction of CSF tracer influx in the dorsolateral cortex and CA1-DG molecular layer. In parallel to these changes increased reactive astrogliosis was observed post-BCAS. To further investigate the mechanisms that may lead to these changes, we measured the pulsation of cortical vessels. BCAS impaired vascular pulsation in pial arteries in WT and Tg-SwDI mice. Our findings show that BCAS influences VCI and that this is paralleled by impaired glymphatic drainage and reduced vascular pulsation. We propose that these additional targets need to be considered when treating VCI.
Alzheimer's Disease and Type 2 Diabetes: A Critical Assessment of the Shared Pathological Traits
Chatterjee S and Mudher A
Alzheimer's Disease and Type 2 Diabetes: A Critical Assessment of the Shared Pathological Traits
Chatterjee S and Mudher A
Alzheimer's disease (AD) and Type 2 Diabetes Mellitus (T2DM) are two of the most prevalent diseases in the elderly population worldwide. A growing body of epidemiological studies suggest that people with T2DM are at a higher risk of developing AD. Likewise, AD brains are less capable of glucose uptake from the surroundings resembling a condition of brain insulin resistance. Pathologically AD is characterized by extracellular plaques of Aβ and intracellular neurofibrillary tangles of hyperphosphorylated tau. T2DM, on the other hand is a metabolic disorder characterized by hyperglycemia and insulin resistance. In this review we have discussed how Insulin resistance in T2DM directly exacerbates Aβ and tau pathologies and elucidated the pathophysiological traits of synaptic dysfunction, inflammation, and autophagic impairments that are common to both diseases and indirectly impact Aβ and tau functions in the neurons. Elucidation of the underlying pathways that connect these two diseases will be immensely valuable for designing novel drug targets for Alzheimer's disease.
Systemic Inflammation Accelerates Changes in Microglial and Synaptic Markers in an Experimental Model of Chronic Neurodegeneration
Chouhan JK, Püntener U, Booth SG and Teeling JL
Systemic Inflammation Accelerates Changes in Microglial and Synaptic Markers in an Experimental Model of Chronic Neurodegeneration
Chouhan JK, Püntener U, Booth SG and Teeling JL
Bacterial infections are a common cause of morbidity and mortality in the elderly, and particularly in individuals with a neurodegenerative disease. Experimental models of neurodegeneration have shown that LPS-induced systemic inflammation increases neuronal damage, a process thought to be mediated by activation of "primed" microglia. The effects of a real systemic bacterial infection on the innate immune cells in the brain and neuronal networks are less well described, and therefore, in this study we use the ME7 prion model to investigate the alterations in microglia activation and phenotype and synaptic markers in response to a low grade, live bacterial infection. Mice with or without a pre-existing ME7 prion-induced neurodegenerative disease were given a single systemic injection of live at early or mid-stage of disease progression. Immune activation markers CD11b and MHCII and pro-inflammatory cytokines were analyzed 4 weeks post-infection. Systemic infection with resulted in an exaggerated inflammatory response when compared to ME7 prion mice treated with saline. These changes to inflammatory markers were most pronounced at mid-stage disease. Analysis of synaptic markers in ME7 prion mice revealed a significant reduction of genes that are associated with early response in synaptic plasticity, extracellular matrix structure and post-synaptic density, but no further reduction following systemic infection. In contrast, analysis of activity-related neuronal receptors involved in development of learning and memory, such as and , showed a significant decrease in response to systemic bacterial challenge. These changes were observed early in the disease progression and associated with reduced burrowing activity. The exaggerated innate immune activation and altered expression of genes linked to synaptic plasticity may contribute to the onset and/or progression of neurodegeneration.