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How do neurons age? A focused review on the aging of the microtubular cytoskeleton
Richardson B, Goedert T, Quraishe S, Deinhardt K and Mudher A
How do neurons age? A focused review on the aging of the microtubular cytoskeleton
Richardson B, Goedert T, Quraishe S, Deinhardt K and Mudher A
Aging is the leading risk factor for Alzheimer's disease and other neurodegenerative diseases. We now understand that a breakdown in the neuronal cytoskeleton, mainly underpinned by protein modifications leading to the destabilization of microtubules, is central to the pathogenesis of Alzheimer's disease. This is accompanied by morphological defects across the somatodendritic compartment, axon, and synapse. However, knowledge of what occurs to the microtubule cytoskeleton and morphology of the neuron during physiological aging is comparatively poor. Several recent studies have suggested that there is an age-related increase in the phosphorylation of the key microtubule stabilizing protein tau, a modification, which is known to destabilize the cytoskeleton in Alzheimer's disease. This indicates that the cytoskeleton and potentially other neuronal structures reliant on the cytoskeleton become functionally compromised during normal physiological aging. The current literature shows age-related reductions in synaptic spine density and shifts in synaptic spine conformation which might explain age-related synaptic functional deficits. However, knowledge of what occurs to the microtubular and actin cytoskeleton, with increasing age is extremely limited. When considering the somatodendritic compartment, a regression in dendrites and loss of dendritic length and volume is reported whilst a reduction in soma volume/size is often seen. However, research into cytoskeletal change is limited to a handful of studies demonstrating reductions in and mislocalizations of microtubule-associated proteins with just one study directly exploring the integrity of the microtubules. In the axon, an increase in axonal diameter and age-related appearance of swellings is reported but like the dendrites, just one study investigates the microtubules directly with others reporting loss or mislocalization of microtubule-associated proteins. Though these are the general trends reported, there are clear disparities between model organisms and brain regions that are worthy of further investigation. Additionally, longitudinal studies of neuronal/cytoskeletal aging should also investigate whether these age-related changes contribute not just to vulnerability to disease but also to the decline in nervous system function and behavioral output that all organisms experience. This will highlight the utility, if any, of cytoskeletal fortification for the promotion of healthy neuronal aging and potential protection against age-related neurodegenerative disease. This review seeks to summarize what is currently known about the physiological aging of the neuron and microtubular cytoskeleton in the hope of uncovering mechanisms underpinning age-related risk to disease.
The RESIST Study: Examining Cognitive Change in Rheumatoid Arthritis Patients with Mild Cognitive Impairment Being Treated with a TNF-Inhibitor Compared to a Conventional Synthetic Disease-Modifying Anti-Rheumatic Drug
Marr C, McDowell B, Holmes C, Edwards CJ, Cardwell C, McHenry M, Meenagh G, Teeling JL and McGuinness B
The RESIST Study: Examining Cognitive Change in Rheumatoid Arthritis Patients with Mild Cognitive Impairment Being Treated with a TNF-Inhibitor Compared to a Conventional Synthetic Disease-Modifying Anti-Rheumatic Drug
Marr C, McDowell B, Holmes C, Edwards CJ, Cardwell C, McHenry M, Meenagh G, Teeling JL and McGuinness B
Evidence suggests that TNF inhibitors (TNFi) used to treat rheumatoid arthritis (RA) may protect against Alzheimer's disease progression by reducing inflammation.
Double-Clad Antiresonant Hollow-Core Fiber and Its Comparison with Other Fibers for Multiphoton Micro-Endoscopy
Szwaj M, Davidson IA, Johnson PB, Jasion G, Jung Y, Sandoghchi SR, Herdzik KP, Bourdakos KN, Wheeler NV, Mulvad HC, Richardson DJ, Poletti F and Mahajan S
Double-Clad Antiresonant Hollow-Core Fiber and Its Comparison with Other Fibers for Multiphoton Micro-Endoscopy
Szwaj M, Davidson IA, Johnson PB, Jasion G, Jung Y, Sandoghchi SR, Herdzik KP, Bourdakos KN, Wheeler NV, Mulvad HC, Richardson DJ, Poletti F and Mahajan S
Label-free and multiphoton micro-endoscopy can transform clinical histopathology by providing an in situ tool for diagnostic imaging and surgical treatment in diseases such as cancer. Key to a multiphoton imaging-based micro-endoscopic device is the optical fiber, for distortion-free and efficient delivery of ultra-short laser pulses to the sample and effective signal collection. In this work, we study a new hollow-core (air-filled) double-clad anti-resonant fiber (DC-ARF) as a high-performance candidate for multiphoton micro-endoscopy. We compare the fiber characteristics of the DC-ARF with a single-clad anti-resonant fiber (SC-ARF) and a solid core fiber (SCF). In this work, while the DC-ARF and the SC-ARF enable low-loss (<0.2 dBm), close to dispersion-free excitation pulse delivery (2000% of pulse width increase at 900 nm per 1 m fiber). An ideal optical fiber endoscope needs to be several meters long and should enable both excitation and collection through the fiber. Therefore, we performed multiphoton imaging on endoscopy-compatible 1 m and 3 m lengths of fiber in the back-scattered geometry, wherein the signals were collected either directly (non-descanned detection) or through the fiber (descanned detection). Second harmonic images were collected from barium titanate crystals as well as from biological samples (mouse tail tendon). In non-descanned detection conditions, the ARFs outperformed the SCF by up to 10 times in terms of signal-to-noise ratio of images. Significantly, only the DC-ARF, due to its high numerical aperture (NA) of 0.45 and wide-collection bandwidth (>1 µm), could provide images in the de-scanned detection configuration desirable for endoscopy. Thus, our systematic characterization and comparison of different optical fibers under different image collection configurations, confirms and establishes the utility of DC-ARFs for high-performing label-free multiphoton imaging-based micro-endoscopy.
Shaping the future of preclinical development of successful disease-modifying drugs against Alzheimer's disease: a systematic review of tau propagation models
Basheer N, Buee L, Brion JP, Smolek T, Muhammadi MK, Hritz J, Hromadka T, Dewachter I, Wegmann S, Landrieu I, Novak P, Mudher A and Zilka N
Shaping the future of preclinical development of successful disease-modifying drugs against Alzheimer's disease: a systematic review of tau propagation models
Basheer N, Buee L, Brion JP, Smolek T, Muhammadi MK, Hritz J, Hromadka T, Dewachter I, Wegmann S, Landrieu I, Novak P, Mudher A and Zilka N
The transcellular propagation of the aberrantly modified protein tau along the functional brain network is a key hallmark of Alzheimer's disease and related tauopathies. Inoculation-based tau propagation models can recapitulate the stereotypical spread of tau and reproduce various types of tau inclusions linked to specific tauopathy, albeit with varying degrees of fidelity. With this systematic review, we underscore the significance of judicious selection and meticulous functional, biochemical, and biophysical characterization of various tau inocula. Furthermore, we highlight the necessity of choosing suitable animal models and inoculation sites, along with the critical need for validation of fibrillary pathology using confirmatory staining, to accurately recapitulate disease-specific inclusions. As a practical guide, we put forth a framework for establishing a benchmark of inoculation-based tau propagation models that holds promise for use in preclinical testing of disease-modifying drugs.
[1-C]-Butanol Positron Emission Tomography reveals an impaired brain to nasal turbinates pathway in aging amyloid positive subjects
Mehta NH, Wang X, Keil SA, Xi K, Zhou L, Lee K, Tan W, Spector E, Goldan A, Kelly J, Karakatsanis NA, Mozley PD, Nehmeh S, Chazen JL, Morin S, Babich J, Ivanidze J, Pahlajani S, Tanzi EB, Saint-Louis L, Butler T, Chen K, Rusinek H, Carare RO, Li Y, Chiang GC and de Leon MJ
[1-C]-Butanol Positron Emission Tomography reveals an impaired brain to nasal turbinates pathway in aging amyloid positive subjects
Mehta NH, Wang X, Keil SA, Xi K, Zhou L, Lee K, Tan W, Spector E, Goldan A, Kelly J, Karakatsanis NA, Mozley PD, Nehmeh S, Chazen JL, Morin S, Babich J, Ivanidze J, Pahlajani S, Tanzi EB, Saint-Louis L, Butler T, Chen K, Rusinek H, Carare RO, Li Y, Chiang GC and de Leon MJ
Reduced clearance of cerebrospinal fluid (CSF) has been suggested as a pathological feature of Alzheimer's disease (AD). With extensive documentation in non-human mammals and contradictory human neuroimaging data it remains unknown whether the nasal mucosa is a CSF drainage site in humans. Here, we used dynamic PET with [1-C]-Butanol, a highly permeable radiotracer with no appreciable brain binding, to test the hypothesis that tracer drainage from the nasal pathway reflects CSF drainage from brain. As a test of the hypothesis, we examined whether brain and nasal fluid drainage times were correlated and affected by brain amyloid.
Patient and public involvement and engagement (PPIE): how valuable and how hard? An evaluation of ALL_EARS@UoS PPIE group, 18 months on
Hough K, Grasmeder M, Parsons H, Jones WB, Smith S, Satchwell C, Hobday I, Taylor S and Newman T
Patient and public involvement and engagement (PPIE): how valuable and how hard? An evaluation of ALL_EARS@UoS PPIE group, 18 months on
Hough K, Grasmeder M, Parsons H, Jones WB, Smith S, Satchwell C, Hobday I, Taylor S and Newman T
ALL_EARS@UoS is a patient and public involvement and engagement (PPIE) group for people with lived experience of hearing loss. The purpose of the group is to share experiences of hearing loss and hearing healthcare, inform research and improve services for patients at University of Southampton Auditory Implant Service. A year after inception, we wanted to critically reflect on the value and challenges of the group. Four members of ALL_EARS@UoS were recruited to an evaluation steering group. This paper reports the evaluation of the group using the UK Standards for Public Involvement.
A Systematic Review and Meta-Analysis of the Pathology Underlying Aneurysm Enhancement on Vessel Wall Imaging
Digpal R, Arkill KP, Doherty R, Yates J, Milne LK, Broomes N, Katsamenis OL, Macdonald J, Ditchfield A, Narata AP, Darekar A, Carare RO, Fabian M, Galea I and Bulters D
A Systematic Review and Meta-Analysis of the Pathology Underlying Aneurysm Enhancement on Vessel Wall Imaging
Digpal R, Arkill KP, Doherty R, Yates J, Milne LK, Broomes N, Katsamenis OL, Macdonald J, Ditchfield A, Narata AP, Darekar A, Carare RO, Fabian M, Galea I and Bulters D
Intracranial aneurysms are common, but only a minority rupture and cause subarachnoid haemorrhage, presenting a dilemma regarding which to treat. Vessel wall imaging (VWI) is a contrast-enhanced magnetic resonance imaging (MRI) technique used to identify unstable aneurysms. The pathological basis of MR enhancement of aneurysms is the subject of debate. This review synthesises the literature to determine the pathological basis of VWI enhancement. PubMed and Embase searches were performed for studies reporting VWI of intracranial aneurysms and their correlated histological analysis. The risk of bias was assessed. Calculations of interdependence, univariate and multivariate analysis were performed. Of 228 publications identified, 7 met the eligibility criteria. Individual aneurysm data were extracted for 72 out of a total of 81 aneurysms. Univariate analysis showed macrophage markers (CD68 and MPO, = 0.001 and = 0.002), endothelial cell markers (CD34 and CD31, = 0.007 and = 0.003), glycans (Alcian blue, = 0.003) and wall thickness ( = 0.030) were positively associated with enhancement. Aneurysm enhancement therefore appears to be associated with inflammatory infiltrate and neovascularisation. However, all these markers are correlated with each other, and the literature is limited in terms of the numbers of aneurysms analysed and the parameters considered. The data are therefore insufficient to determine if these associations are independent of each other or of aneurysm size, wall thickness and rupture status. Thus, the cause of aneurysm-wall enhancement currently remains unknown.
Distinctive retinal peri-arteriolar versus peri-venular amyloid plaque distribution correlates with the cognitive performance
Dumitrascu OM, Doustar J, Fuchs DT, Koronyo Y, Sherman DS, Miller MS, Johnson KO, Carare RO, Verdooner SR, Lyden PD, Schneider JA, Black KL and Koronyo-Hamaoui M
Distinctive retinal peri-arteriolar versus peri-venular amyloid plaque distribution correlates with the cognitive performance
Dumitrascu OM, Doustar J, Fuchs DT, Koronyo Y, Sherman DS, Miller MS, Johnson KO, Carare RO, Verdooner SR, Lyden PD, Schneider JA, Black KL and Koronyo-Hamaoui M
The vascular contribution to Alzheimer's disease (AD) is tightly connected to cognitive performance across the AD continuum. We topographically describe retinal perivascular amyloid plaque (AP) burden in subjects with normal or impaired cognition.
Markers of adipose tissue fibrogenesis associate with clinically significant liver fibrosis and are unchanged by synbiotic treatment in patients with NAFLD
Bilson J, Oquendo CJ, Read J, Scorletti E, Afolabi PR, Lord J, Bindels LB, Targher G, Mahajan S, Baralle D, Calder PC, Byrne CD and Sethi JK
Markers of adipose tissue fibrogenesis associate with clinically significant liver fibrosis and are unchanged by synbiotic treatment in patients with NAFLD
Bilson J, Oquendo CJ, Read J, Scorletti E, Afolabi PR, Lord J, Bindels LB, Targher G, Mahajan S, Baralle D, Calder PC, Byrne CD and Sethi JK
Subcutaneous adipose tissue (SAT) dysfunction contributes to NAFLD pathogenesis and may be influenced by the gut microbiota. Whether transcript profiles of SAT are associated with liver fibrosis and are influenced by synbiotic treatment (that changes the gut microbiome) is unknown. We investigated: (a) whether the presence of clinically significant, ≥F2 liver fibrosis associated with adipose tissue (AT) dysfunction, differential gene expression in SAT, and/or a marker of tissue fibrosis (Composite collagen gene expression (CCGE)); and (b) whether synbiotic treatment modified markers of AT dysfunction and the SAT transcriptome.
Mechanisms of SARS-CoV-2 Inactivation Using UVC Laser Radiation
Devitt G, Johnson PB, Hanrahan N, Lane SIR, Vidale MC, Sheth B, Allen JD, Humbert MV, Spalluto CM, Hervé RC, Staples K, West JJ, Forster R, Divecha N, McCormick CJ, Crispin M, Hempler N, Malcolm GPA and Mahajan S
Mechanisms of SARS-CoV-2 Inactivation Using UVC Laser Radiation
Devitt G, Johnson PB, Hanrahan N, Lane SIR, Vidale MC, Sheth B, Allen JD, Humbert MV, Spalluto CM, Hervé RC, Staples K, West JJ, Forster R, Divecha N, McCormick CJ, Crispin M, Hempler N, Malcolm GPA and Mahajan S
Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) has had a tremendous impact on humanity. Prevention of transmission by disinfection of surfaces and aerosols through a chemical-free method is highly desirable. Ultraviolet C (UVC) light is uniquely positioned to achieve inactivation of pathogens. We report the inactivation of SARS-CoV-2 virus by UVC radiation and explore its mechanisms. A dose of 50 mJ/cm using a UVC laser at 266 nm achieved an inactivation efficiency of 99.89%, while infectious virions were undetectable at 75 mJ/cm indicating >99.99% inactivation. Infection by SARS-CoV-2 involves viral entry mediated by the spike glycoprotein (S), and viral reproduction, reliant on translation of its genome. We demonstrate that UVC radiation damages ribonucleic acid (RNA) and provide in-depth characterization of UVC-induced damage of the S protein. We find that UVC severely impacts SARS-CoV- 2 spike protein's ability to bind human angiotensin-converting enzyme 2 (hACE2) and this correlates with loss of native protein conformation and aromatic amino acid integrity. This report has important implications for the design and development of rapid and effective disinfection systems against the SARS-CoV-2 virus and other pathogens.
Amyloid Beta Oligomers Activate Death Receptors and Mitochondria-Mediated Apoptotic Pathways in Cerebral Vascular Smooth Muscle Cells; Protective Effects of Carbonic Anhydrase Inhibitors
Anzovino A, Canepa E, Alves M, Lemon NL, Carare RO and Fossati S
Amyloid Beta Oligomers Activate Death Receptors and Mitochondria-Mediated Apoptotic Pathways in Cerebral Vascular Smooth Muscle Cells; Protective Effects of Carbonic Anhydrase Inhibitors
Anzovino A, Canepa E, Alves M, Lemon NL, Carare RO and Fossati S
Amyloid beta (Aβ) deposition within the brain vasculature is an early hallmark of Alzheimer's disease (AD), which triggers loss of brain vascular smooth muscle cells (BVSMCs) in cerebral arteries, via poorly understood mechanisms, altering cerebral blood flow, brain waste clearance, and promoting cognitive impairment. We have previously shown that, in brain endothelial cells (ECs), vasculotropic Aβ species induce apoptosis through death receptors (DRs) DR4 and DR5 and mitochondria-mediated mechanisms, while FDA-approved carbonic anhydrase inhibitors (CAIs) prevent mitochondria-mediated EC apoptosis in vitro and in vivo. In this study, we analyzed Aβ-induced extrinsic and intrinsic (DR- and mitochondria-mediated) apoptotic pathways in BVSMC, aiming to unveil new therapeutic targets to prevent BVSMC stress and death. We show that both apoptotic pathways are activated in BVSMCs by oligomeric Aβ42 and and mitochondrial respiration is severely impaired. Importantly, the CAIs methazolamide (MTZ) and acetazolamide (ATZ) prevent the pro-apoptotic effects in BVSMCs, while reducing caspase 3 activation and Aβ deposition in the arterial walls of TgSwDI animals, a murine model of cerebral amyloid angiopathy (CAA). This study reveals new molecular targets and a promising therapeutic strategy against BVSMC dysfunction in AD, CAA, and ARIA (amyloid-related imaging abnormalities) complications of recently FDA-approved anti-Aβ antibodies.
Development of hydrogel-based standards and phantoms for non-linear imaging at depth
Haseeb F, Bourdakos KN, Forsyth E, Setchfield K, Gorman A, Venkateswaran S, Wright AJ, Mahajan S and Bradley M
Development of hydrogel-based standards and phantoms for non-linear imaging at depth
Haseeb F, Bourdakos KN, Forsyth E, Setchfield K, Gorman A, Venkateswaran S, Wright AJ, Mahajan S and Bradley M
Rapid advances in medical imaging technology, particularly the development of optical systems with non-linear imaging modalities, are boosting deep tissue imaging. The development of reliable standards and phantoms is critical for validation and optimization of these cutting-edge imaging techniques.
Topical Cellular/Tissue and Molecular Aspects Regarding Nonpharmacological Interventions in Alzheimer's Disease-A Systematic Review
Aurelian S, Ciobanu A, Cărare R, Stoica SI, Anghelescu A, Ciobanu V, Onose G, Munteanu C, Popescu C, Andone I, Spînu A, Firan C, Cazacu IS, Trandafir AI, Băilă M, Postoiu RL and Zamfirescu A
Topical Cellular/Tissue and Molecular Aspects Regarding Nonpharmacological Interventions in Alzheimer's Disease-A Systematic Review
Aurelian S, Ciobanu A, Cărare R, Stoica SI, Anghelescu A, Ciobanu V, Onose G, Munteanu C, Popescu C, Andone I, Spînu A, Firan C, Cazacu IS, Trandafir AI, Băilă M, Postoiu RL and Zamfirescu A
One of the most complex and challenging developments at the beginning of the third millennium is the alarming increase in demographic aging, mainly-but not exclusively-affecting developed countries. This reality results in one of the harsh medical, social, and economic consequences: the continuously increasing number of people with dementia, including Alzheimer's disease (AD), which accounts for up to 80% of all such types of pathology. Its large and progressive disabling potential, which eventually leads to death, therefore represents an important public health matter, especially because there is no known cure for this disease. Consequently, periodic reappraisals of different therapeutic possibilities are necessary. For this purpose, we conducted this systematic literature review investigating nonpharmacological interventions for AD, including their currently known cellular and molecular action bases. This endeavor was based on the PRISMA method, by which we selected 116 eligible articles published during the last year. Because of the unfortunate lack of effective treatments for AD, it is necessary to enhance efforts toward identifying and improving various therapeutic and rehabilitative approaches, as well as related prophylactic measures.
All-fiberized 1840-nm femtosecond thulium fiber laser for label-free nonlinear microscopy
Xu D, Bourdakos KN, Crisford A, Johnson P, Abughazaleh I, Srisamran P, Oreffo ROC, Mahajan S, Richardson DJ and Xu L
All-fiberized 1840-nm femtosecond thulium fiber laser for label-free nonlinear microscopy
Xu D, Bourdakos KN, Crisford A, Johnson P, Abughazaleh I, Srisamran P, Oreffo ROC, Mahajan S, Richardson DJ and Xu L
We report an all-fiberized 1840-nm thulium-fiber-laser source, comprising a dissipative-soliton mode-locked seed laser and a chirped-pulse-amplification system for label-free biological imaging through nonlinear microscopy. The mode-locked thulium fiber laser generated dissipative-soliton pulses with a pre-chirped duration of 7 ps and pulse energy of 1 nJ. A chirped-pulse fiber-amplification system employing an in-house-fabricated, short-length, single-mode, high-absorption, thulium fiber delivered pulses with energies up to 105 nJ. The pulses were capable of being compressed to 416 fs by passing through a grating pair. Imaging of mouse tissue and human bone samples was demonstrated using this source via third-harmonic generation microscopy.
Leveraging real-world data to improve cochlear implant outcomes: Is the data available?
Findlay C, Edwards M, Hough K, Grasmeder M and Newman TA
Leveraging real-world data to improve cochlear implant outcomes: Is the data available?
Findlay C, Edwards M, Hough K, Grasmeder M and Newman TA
A small but persistent proportion of individuals do not gain the expected benefit from cochlear implants(CI). A step-change in the understanding of factors affecting outcomes could come through data science. This study evaluates clinical data capture to assess the quality and utility of CI user's health records for data science, by assessing the recording of otitis media. Otitis media was selected as it is associated with the development of sensorineural hearing loss and may affect cochlear implant outcomes.
A laser-induced mouse model of progressive retinal degeneration with central sparing displays features of parafoveal geographic atrophy
Khan AH, Soundara Pandi SP, Scott JA, Sánchez-Bretaño A, Lynn SA, Ratnayaka JA, Teeling JL and Lotery AJ
A laser-induced mouse model of progressive retinal degeneration with central sparing displays features of parafoveal geographic atrophy
Khan AH, Soundara Pandi SP, Scott JA, Sánchez-Bretaño A, Lynn SA, Ratnayaka JA, Teeling JL and Lotery AJ
There are no disease-modifying treatments available for geographic atrophy (GA), the advanced form of dry age-related macular degeneration. Current murine models fail to fully recapitulate the features of GA and thus hinder drug discovery. Here we describe a novel mouse model of retinal degeneration with hallmark features of GA. We used an 810 nm laser to create a retinal lesion with central sparing (RLCS), simulating parafoveal atrophy observed in patients with progressive GA. Laser-induced RLCS resulted in progressive GA-like pathology with the development of a confluent atrophic lesion. We demonstrate significant changes to the retinal structure and thickness in the central unaffected retina over a 24-week post-laser period, confirmed by longitudinal optical coherence tomography scans. We further show characteristic features of progressive GA, including a gradual reduction in the thickness of the central, unaffected retina and of total retinal thickness. Histological changes observed in the RLCS correspond to GA pathology, which includes the collapse of the outer nuclear layer, increased numbers of GFAP + , CD11b + and FcγRI + cells, and damage to cone and rod photoreceptors. We demonstrate a laser-induced mouse model of parafoveal GA progression, starting at 2 weeks post-laser and reaching confluence at 24 weeks post-laser. This 24-week time-frame in which GA pathology develops, provides an extended window of opportunity for proof-of-concept evaluation of drugs targeting GA. This time period is an added advantage compared to several existing models of geographic atrophy.
An Exploratory Study Provides Insights into MMP9 and Aβ Levels in the Vitreous and Blood across Different Ages and in a Subset of AMD Patients
Lynn SA, Soubigou F, Dewing JM, Smith A, Ballingall J, Sass T, Nica I, Watkins C, Gupta B, Almuhtaseb H, Lash SC, Yuen HM, Cree A, Newman TA, Lotery AJ and Ratnayaka JA
An Exploratory Study Provides Insights into MMP9 and Aβ Levels in the Vitreous and Blood across Different Ages and in a Subset of AMD Patients
Lynn SA, Soubigou F, Dewing JM, Smith A, Ballingall J, Sass T, Nica I, Watkins C, Gupta B, Almuhtaseb H, Lash SC, Yuen HM, Cree A, Newman TA, Lotery AJ and Ratnayaka JA
Matrix metalloproteinase-9 (MMP9) and total amyloid-beta (Aβ) are prospective biomarkers of ocular ageing and retinopathy. These were quantified by ELISA in the vitreous and blood from controls ( = 55) and in a subset of age-related macular degeneration (AMD) patients ( = 12) for insights and possible additional links between the ocular and systemic compartments. Vitreous MMP9 levels in control and AMD groups were 932.5 ± 240.9 pg/mL and 813.7 ± 157.6 pg/mL, whilst serum levels were 2228 ± 193 pg/mL and 2386.8 ± 449.4 pg/mL, respectively. Vitreous Aβ in control and AMD groups were 1173.5 ± 117.1 pg/mL and 1275.6 ± 332.9 pg/mL, whilst plasma Aβ were 574.3 ± 104.8 pg/mL and 542.2 ± 139.9 pg/mL, respectively. MMP9 and Aβ showed variable levels across the lifecourse, indicating no correlation to each other or with age nor AMD status, though the smaller AMD cohort was a limiting factor. Aβ and MMP9 levels in the vitreous and blood were unrelated to mean arterial pressure. Smoking, another modifiable risk, showed no association with vitreous Aβ. However, smoking may be linked with vitreous ( = 0.004) and serum ( = 0.005) MMP9 levels in control and AMD groups, though this did not reach our elevated ( = 0.001) significance. A bioinformatics analysis revealed promising MMP9 and APP/Aβ partners for further scrutiny, many of which are already linked with retinopathy.
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 2Â 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.
Biomarkers of Inflammation Increase with Tau and Neurodegeneration but not with Amyloid-β in a Heterogenous Clinical Cohort
Michopoulou S, Prosser A, Kipps C, Dickson J, Guy M and Teeling J
Biomarkers of Inflammation Increase with Tau and Neurodegeneration but not with Amyloid-β in a Heterogenous Clinical Cohort
Michopoulou S, Prosser A, Kipps C, Dickson J, Guy M and Teeling J
Neuroinflammation is an integral part of Alzheimer's disease (AD) pathology. Inflammatory mediators can exacerbate the production of amyloid-β (Aβ), the propagation of tau pathology and neuronal loss.
Tau-mediated axonal degeneration is prevented by activation of the Wld pathway
Stubbs K, Batchelor B, Sivanantharajah L, Sealey M, Ramirez-Moreno M, Ruiz E, Richardson B, Perry VH, Newman TA and Mudher A
Tau-mediated axonal degeneration is prevented by activation of the Wld pathway
Stubbs K, Batchelor B, Sivanantharajah L, Sealey M, Ramirez-Moreno M, Ruiz E, Richardson B, Perry VH, Newman TA and Mudher A
Tauopathy is characterized by neuronal dysfunction and degeneration occurring as a result of changes to the microtubule-associated protein tau. The neuronal changes evident in tauopathy bear striking morphological resemblance to those reported in models of Wallerian degeneration. The mechanisms underpinning Wallerian degeneration are not fully understood although it can be delayed by the expression of the slow Wallerian degeneration (Wld) protein, which has also been demonstrated to delay axonal degeneration in some models of neurodegenerative disease. Given the morphological similarities between tauopathy and Wallerian degeneration, this study investigated whether tau-mediated phenotypes can be modulated by co-expression of Wld. In a model of tauopathy in which expression of human 0N3R tau protein leads to progressive age-dependent phenotypes, Wld was expressed with and without activation of the downstream pathway. The olfactory receptor neuron circuit was used for these studies in adults, and the larval motor neuron system was employed in larvae. Tau phenotypes studied included neurodegeneration, axonal transport, synaptic deficits and locomotor behaviour. Impact on total tau was ascertained by assessing total, phosphorylated and misfolded tau levels by immunohistochemistry. Activation of the pathway downstream of Wld completely suppressed tau-mediated degeneration. This protective effect was evident even if the pathway downstream of Wld was activated several weeks after tau-mediated degeneration had become established. Though total tau levels were not altered, the protected neurons displayed significantly reduced MC1 immunoreactivity suggestive of clearance of misfolded tau, as well as a trend for a decline in tau species phosphorylated at the AT8 and PHF1 epitopes. In contrast, Wld expression without activation of the downstream protective pathway did not rescue tau-mediated degeneration in adults or improve tau-mediated neuronal dysfunction including deficits in axonal transport, synaptic alterations and locomotor behaviour in tau-expressing larvae. This collectively implies that the pathway mediating the protective effect of Wld intersects with the mechanism(s) of degeneration initiated by tau and can effectively halt tau-mediated degeneration at both early and late stages. Understanding the mechanisms underpinning this protection could identify much-needed disease-modifying targets for tauopathies.
Age-related changes in tau and autophagy in human brain in the absence of neurodegeneration
Chatterjee S, Sealey M, Ruiz E, Pegasiou CM, Brookes K, Green S, Crisford A, Duque-Vasquez M, Luckett E, Robertson R, Richardson P, Vajramani G, Grundy P, Bulters D, Proud C, Vargas-Caballero M and Mudher A
Age-related changes in tau and autophagy in human brain in the absence of neurodegeneration
Chatterjee S, Sealey M, Ruiz E, Pegasiou CM, Brookes K, Green S, Crisford A, Duque-Vasquez M, Luckett E, Robertson R, Richardson P, Vajramani G, Grundy P, Bulters D, Proud C, Vargas-Caballero M and Mudher A
Tau becomes abnormally hyper-phosphorylated and aggregated in tauopathies like Alzheimers disease (AD). As age is the greatest risk factor for developing AD, it is important to understand how tau protein itself, and the pathways implicated in its turnover, change during aging. We investigated age-related changes in total and phosphorylated tau in brain samples from two cohorts of cognitively normal individuals spanning 19-74 years, without overt neurodegeneration. One cohort utilised resected tissue and the other used post-mortem tissue. Total soluble tau levels declined with age in both cohorts. Phosphorylated tau was undetectable in the post-mortem tissue but was clearly evident in the resected tissue and did not undergo significant age-related change. To ascertain if the decline in soluble tau was correlated with age-related changes in autophagy, three markers of autophagy were tested but only two appeared to increase with age and the third was unchanged. This implies that in individuals who do not develop neurodegeneration, there is an age-related reduction in soluble tau which could potentially be due to age-related changes in autophagy. Thus, to explore how an age-related increase in autophagy might influence tau-mediated dysfunctions in vivo, autophagy was enhanced in a Drosophila model and all age-related tau phenotypes were significantly ameliorated. These data shed light on age-related physiological changes in proteins implicated in AD and highlights the need to study pathways that may be responsible for these changes. It also demonstrates the therapeutic potential of interventions that upregulate turnover of aggregate-prone proteins during aging.
Curcumin as a Holistic Treatment for Tau Pathology
Sivanantharajah L and Mudher A
Curcumin as a Holistic Treatment for Tau Pathology
Sivanantharajah L and Mudher A
Global forecasts for prevalence of Alzheimer's Disease (AD) estimate that 152.8 million people will have dementia in 2050, a sharp rise from 57.4 million in 2019 (GBD 2019). This rise can be attributable to increases in population growth and aging, but in the absence of disease-modifying therapies it poses a huge societal challenge that must be addressed urgently. One way to combat this challenge is to explore the utility of holistic treatments that may protect against AD, including traditional herbs, spices and other nutraceuticals that are pharmacologically safe, inexpensive and readily available. In this light, the spice turmeric, and its active ingredient curcumin, has been investigated as a potential holistic treatment for AD over the past 2 decades; however, promising results with animal studies have not translated to success in clinical trials. One issue is that most animal models examining the effects of curcumin and curcumin derivatives in AD have been done with a focus at ameliorating amyloid pathology. Due to the limited success of Amyloid-β-based drugs in recent clinical trials, tau-focused therapeutics provide a promising alternative. In this article, we aim to provide a clearer picture of what is currently known about the effectiveness of curcumin and curcumin derivatives to ameliorate tau pathology. Tau focused studies may help inform more successful clinical studies by placing greater emphasis on the development and optimised delivery of curcumin derivatives that more effectively target tau pathology.
Perfusion Imaging and Inflammation Biomarkers Provide Complementary Information in Alzheimer's Disease
Michopoulou S, Prosser A, Dickson J, Guy M, Teeling JL and Kipps C
Perfusion Imaging and Inflammation Biomarkers Provide Complementary Information in Alzheimer's Disease
Michopoulou S, Prosser A, Dickson J, Guy M, Teeling JL and Kipps C
Single photon emission tomography (SPECT) can detect early changes in brain perfusion to support the diagnosis of dementia. Inflammation is a driver for dementia progression and measures of inflammation may further support dementia diagnosis.