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Recent publications
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.
[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.
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.
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.
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.
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.
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.
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.
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.
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.
Human Tau Aggregates Are Permissive to Protein Synthesis-Dependent Memory in Tauopathy Models
Vourkou E, Rouiz Ortega ED, Mahajan S, Mudher A and Skoulakis EMC
Human Tau Aggregates Are Permissive to Protein Synthesis-Dependent Memory in Tauopathy Models
Vourkou E, Rouiz Ortega ED, Mahajan S, Mudher A and Skoulakis EMC
Tauopathies including Alzheimer's disease, are characterized by progressive cognitive decline, neurodegeneration, and intraneuronal aggregates comprised largely of the axonal protein Tau. It has been unclear whether cognitive deficits are a consequence of aggregate accumulation thought to compromise neuronal health and eventually lead to neurodegeneration. We use the tauopathy model and mixed-sex populations to reveal an adult onset pan-neuronal Tau accumulation-dependent decline in learning efficacy and a specific defect in protein synthesis-dependent memory (PSD-M), but not in its protein synthesis-independent variant. We demonstrate that these neuroplasticity defects are reversible on suppression of new transgenic human Tau expression and surprisingly correlate with an increase in Tau aggregates. Inhibition of aggregate formation via acute oral administration of methylene blue results in re-emergence of deficient memory in animals with suppressed human Tau (hTau) expression. Significantly, aggregate inhibition results in PSD-M deficits in hTau-expressing animals, which present elevated aggregates and normal memory if untreated with methylene blue. Moreover, methylene blue-dependent hTau aggregate suppression within adult mushroom body neurons also resulted in emergence of memory deficits. Therefore, deficient PSD-M on human Tau expression in the CNS is not a consequence of toxicity and neuronal loss because it is reversible. Furthermore, PSD-M deficits do not result from aggregate accumulation, which appears permissive, if not protective of processes underlying this memory variant. Intraneuronal Tau aggregate accumulation has been proposed to underlie the cognitive decline and eventual neurotoxicity that characterizes the neurodegenerative dementias known as tauopathies. However, we show in three experimental settings that Tau aggregates in the CNS do not impair but rather appear to facilitate processes underlying protein synthesis-dependent memory within affected neurons.
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.
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.
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.