IntroductionTau pathology is associated with a number of age-related neurodegenerative disorders. Few treatments have been demonstrated to diminish the impact of tau pathology in mouse models and none are yet effective in humans. Histone deacetylase 6 (HDAC6) is an enzyme that removes acetyl groups from cytoplasmic proteins, rather than nuclear histones. Its substrates include tubulin, heat shock protein 90 and cortactin. Tubastatin A is a selective inhibitor of HDAC6. Modification of tau pathology by specific inhibition of HDAC6 presents a potential therapeutic approach in tauopathy.MethodsWe treated rTg4510 mouse models of tau deposition and non-transgenic mice with tubastatin (25 mg/kg) or saline (0.9%) from 5 to 7 months of age. Cognitive behavior analysis, histology and biochemical analysis were applied to access the effect of tubastatin on memory, tau pathology and neurodegeneration (hippocampal volume).ResultsWe present data showing that tubastatin restored memory function in rTg4510 mice and reversed a hyperactivity phenotype. We further found that tubastatin reduced the levels of total tau, both histologically and by western analysis. Reduction in total tau levels was positively correlated with memory improvement in these mice. However, there was no impact on phosphorylated forms of tau, either by histology or western analysis, nor was there an impact on silver positive inclusions histologically.ConclusionPotential mechanisms by which HDAC6 inhibitors might benefit the rTg4510 mouse include stabilization of microtubules secondary to increased tubulin acetylation, increased degradation of tau secondary to increased acetylation of HSP90 or both. These data support the use of HDAC6 inhibitors as potential therapeutic agents against tau pathology.
BackgroundMiddle meningeal artery (MMA) embolization is an emerging therapy for the resolution of subacute or chronic subdural hematoma (CSDH). CSDH patients are often elderly and have several comorbidities. We evaluated our experience with transradial access (TRA) for MMA embolization using predominantly Onyx under conscious sedation.MethodsData for consecutive patients who underwent transradial MMA embolization for CSDH during a 2-year period (2018–2019) were analyzed from a single-center, prospectively-maintained database. Patient demographics, comorbidities, ambulatory times, subdural hematoma resorption status, and guide catheter type were recorded. Conversion to femoral access and complication rates were also recorded. Univariate and multivariate analyses were performed.ResultsForty-six patients (mean age, 71.7±14.4 years) were included in this study. Mean CSDH size was 14±5.5 mm. Most (91.3%) TRA embolizations were performed with 6-French 0.071-inch Benchmark guide catheters (Penumbra). MMA embolization was successful in 44 patients (95.7%) (including two cases of TRA conversion). Twenty-one (48%) patients had a severe Charlson Comorbidity Index (>5). Symptomatic improvement was noted in 39 of 44 patients (88.6%). Mean length of stay was 4±3 days. Patients were ambulated immediately postprocedure. At mean follow-up (8±4 weeks), 86.4% of patients had complete or partial CSDH resolution. Persistent use of antiplatelet agents after the procedure was associated with failed or minimal CSDH resorption (5 of 6, 83.3% vs 9 of 38 23.7% with complete or near-complete resolution; P=0.009).ConclusionTransradial Onyx MMA embolization under conscious sedation is safe and effective for CSDH treatment. TRA may be especially useful in elderly patients with numerous comorbidities.
BackgroundAbnormal tau hyperphosphorylation and its accumulation into intra-neuronal neurofibrillary tangles are linked to neurodegeneration in Alzheimer’s disease and similar tauopathies. One strategy to reduce accumulation is through immunization, but the most immunogenic tau epitopes have so far remained unknown. To fill this gap, we immunized mice with recombinant tau to build a map of the most immunogenic tau epitopes.MethodsNon-transgenic and rTg4510 tau transgenic mice aged 5 months were immunized with either human wild-type tau (Wt, 4R0N) or P301L tau (4R0N). Each protein was formulated in Quil A adjuvant. Sera and splenocytes of vaccinated mice were collected to assess the humoral and cellular immune responses to tau. We employed a peptide array assay to identify the most effective epitopes. Brain histology was utilized to measure the effects of vaccination on tau pathology and inflammation.ResultsHumoral immune responses following immunization demonstrated robust antibody titers (up to 1:80,000 endpoint titers) to each tau species in both mice models. The number of IFN-γ producing T cells and their proliferation were also increased in splenocytes from immunized mice, indicating an increased cellular immune response, and tau levels and neuroinflammation were both reduced. We identified five immunogenic motifs within either the N-terminal (9-15 and 21-27 amino acids), proline rich (168-174 and 220-228 amino acids), or the C-terminal regions (427-438 amino acids) of the wild-type and P301L tau protein sequence.ConclusionsOur study identifies five previously unknown immunogenic motifs of wild-type and mutated (P301L) tau protein. Immunization with both proteins resulted in reduced tau pathology and neuroinflammation in a tau transgenic model, supporting the efficacy of tau immunotherapy in tauopathy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-014-0152-0) contains supplementary material, which is available to authorized users.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.