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Despite the wide range of applications of mRNA therapies, major difficulties exist in the efficient delivery of mRNA into oligodendrocytes, a type of glial cell in the brain. Commonly used viral vectors are not efficient in transforming oligodendrocytes. In this study, we introduced mRNAs into oligodendrocytes with high efficiency and specificity using LUNAR lipid nanoparticles. The uptake of LUNAR lipid nanoparticles occurred via low-density lipoprotein receptors in the presence of apoprotein E. A single dose of LUNAR-human galactosylceramidase mRNA significantly improved phenotypes and survival of twitcher mice, a mouse model of Krabbe disease wherein oligodendrocytes are damaged by galactosylceramidase deficiency. This approach to mRNA therapeutics, combined with cell-specific nanocarriers, demonstrates remarkable potential for the treatment of neurological disorders associated with oligodendrocytes.

Abstract Multiple system atrophy (MSA) is pathologically characterized by the presence of fibrillar α-synuclein-immunoreactive inclusions in oligodendrocytes. Although the myelinating process of oligodendrocytes can be observed in adult human brains, little is known regarding the presence of α-synuclein pathology in immature oligodendrocytes and how their maturation and myelination are affected in MSA brains. Recently, breast carcinoma amplified sequence 1 (BCAS1) has been found to be specifically expressed in immature oligodendrocytes undergoing maturation and myelination. Here, we analyzed the altered dynamics of oligodendroglial maturation in both MSA brains and primary oligodendroglial cell cultures which were incubated with α-synuclein pre-formed fibrils. The numbers of BCAS1-expressing oligodendrocytes that displayed a matured morphology negatively correlated with the density of pathological inclusions in MSA brains but not with that in Parkinson’s disease and diffuse Lewy body disease. In addition, a portion of the BCAS1-expressing oligodendrocyte population showed cytoplasmic inclusions, which were labeled with antibodies against phosphorylated α-synuclein and cleaved caspase-9. Further in vitro examination indicated that the α-synuclein pre-formed fibrils induced cytoplasmic inclusions in the majority of BCAS1-expressing oligodendrocytes. In contrast, the majority of BCAS1-non-expressing mature oligodendrocytes did not develop inclusions on day 4 after maturation induction. Furthermore, exposure of α-synuclein pre-formed fibrils in the BCAS1-positive phase caused a reduction in oligodendroglial cell viability. Our results indicated that oligodendroglial maturation and myelination are impaired in the BCAS1-positive phase of MSA brains, which may lead to the insufficient replacement of defective oligodendrocytes. In vitro, the high susceptibility of BCAS1-expressing primary oligodendrocytes to the extracellular α-synuclein pre-formed fibrils suggests the involvement of insufficient oligodendroglial maturation in MSA disease progression and support the hypothesis that the BCAS1-positive oligodendrocyte lineage cells are prone to take up aggregated α-synuclein in vivo.

Introduction Alzheimer’s disease (AD) is one of the most common causes of dementia. Pathogenic variants in the presenilin 1 (PSEN1) gene are the most frequent cause of early-onset AD. Medications for patients with AD bearing PSEN1 mutation (PSEN1-AD) are limited to symptomatic therapies and no established radical treatments are available. Induced pluripotent stem cell (iPSC)-based drug repurposing identified bromocriptine as a therapeutic candidate for PSEN1-AD. In this study, we used an enrichment strategy with iPSCs to select the study population, and we will investigate the safety and efficacy of an orally administered dose of bromocriptine in patients with PSEN1-AD.Methods and analysis This is a multicentre, randomised, placebo-controlled trial. AD patients with PSEN1 mutations and a Mini Mental State Examination-Japanese score of ≤25 will be randomly assigned, at a 2:1 ratio, to the trial drug or placebo group (≥4 patients in TW-012R and ≥2 patients in placebo). This clinical trial consists of a screening period, double-blind phase (9 months) and extension phase (3 months). The double-blind phase for evaluating the efficacy and safety is composed of the low-dose maintenance period (10 mg/day), high-dose maintenance period (22.5 mg/day) and tapering period of the trial drug. Additionally, there is an open-labelled active drug extension period for evaluating long-term safety. Primary outcomes are safety and efficacy in cognitive and psychological function. Also, exploratory investigations for the efficacy of bromocriptine by neurological scores and biomarkers will be conducted.Ethics and dissemination The proposed trial is conducted according to the Declaration of Helsinki, and was approved by the Institutional Review Board (K070). The study results are expected to be disseminated at international or national conferences and published in international journals following the peer-review process.Trial registration number jRCT2041200008, NCT04413344.

The susceptibility to neurological and psychiatric disorders reveals sexual dimorphism in the structure and function of human brains. Recent evidence has also demonstrated the sex-related differences in cellular components of the brain, including neurons, microglia, astrocytes, and endothelial cells. Oligodendrocyte precursor cells (OPCs) regulate the neuronal system in various ways and play crucial roles in brain homeostasis beyond their well-known role as a reservoir for mature oligodendrocytes. Although recent studies have shown regional diversities and heterogeneities of OPCs, sex-related differences in OPCs are largely unknown. Here, we revealed transcriptomic differences in OPCs isolated from male and female neonatal rat brains. Furthermore, we demonstrated sex-dependent differences in OPCs regarding proliferation, migration, differentiation, tolerance against ischemic stress, energy metabolism, and the ability to regulate the blood–brain barrier integrity.

Background: Large-scale clinical trials have analyzed risk factors for any ischemic stroke in patients with atrial fibrillation (AF). However, the risk factors for cardioembolic stroke (CES), specifically, have not been reported. To clarify the risk factors for CES and clinically significant cardioembolic infarction, we examined the incidence of CES and larger infarct volume (IV) (> 30 mL) CES, employing the Fushimi AF Registry, a community-based prospective cohort of AF patients in the Fushimi ward, Kyoto, Japan. Methods: A total of 4,182 Fushimi AF patients were enrolled from March 2011 to December 2014. The risk factors for CES were evaluated using multivariate analysis. Results: Of 4,182 patients enrolled, 3,749 patients were observed for ≥1 year. During the follow-up period (mean duration, 979 ± 7.7 days), 91/3,749 patients experienced a CES (2.43%). Significant risk factors associated with CES were older age (odds ratio [OR], 1.31; 95% confidence interval [CI], 1.01–1.72; p = 0.046), low body weight (OR, 1.30; 95% CI, 1.03–1.65; p = 0.033), sustained AF (OR, 1.67; 95% CI, 1.05–2.71; p = 0.034), and previous stroke or transient ischemic attack (TIA) (OR, 1.94; 95% CI, 1.22–3.06; p = 0.004). Predictors of a large IV were chronic kidney disease (CKD) (OR, 2.08; 95% CI, 1.09–4.05; p = 0.027) and previous stroke/TIA (OR, 2.27; 95% CI, 1.19–4.24; p = 0.011). Conclusions: In this population-based cohort of Japanese patients with AF, in addition to previous stroke/TIA and older age, sustained AF and low body weight emerged as risk factors for CES, as opposed to any stroke, which may have a different risk profile. Patients with CKD or previous stroke/TIA who developed cardioembolic infarction exhibited more advanced severity. There is a need for direct oral anticoagulants that can be used safely in patients with comorbid AF and CKD.

Background Oligodendrocyte precursor cells (OPCs) regulate neuronal, glial, and vascular systems in diverse ways and display phenotypic heterogeneity beyond their established role as a reservoir for mature oligodendrocytes. However, the detailed phenotypic changes of OPCs after cerebral ischemia remain largely unknown. Here, we aimed to investigate the roles of reactive OPCs in the ischemic brain. Methods and Results The behavior of OPCs was evaluated in a mouse model of ischemic stroke produced by transient middle cerebral artery occlusion in vivo. For in vitro experiments, the phenotypic change of OPCs after oxygen glucose derivation was examined using a primary rat OPC culture. Furthermore, the therapeutic potential of hypoxic OPCs was evaluated in a mouse model of middle cerebral artery occlusion in vivo. Perivascular OPCs in the cerebral cortex were increased alongside poststroke angiogenesis in a mouse model of middle cerebral artery occlusion. In vitro RNA‐seq analysis revealed that primary cultured OPCs increased the gene expression of numerous pro‐angiogenic factors after oxygen glucose derivation. Hypoxic OPCs secreted a greater amount of pro‐angiogenic factors, such as vascular endothelial growth factor and angiopoietin‐1, compared with normoxic OPCs. Hypoxic OPC‐derived conditioned media increased the viability and tube formation of endothelial cells. In vivo studies also demonstrated that 5 consecutive daily treatments with hypoxic OPC‐conditioned media, beginning 2 days after middle cerebral artery occlusion, facilitated poststroke angiogenesis, alleviated infarct volume, and improved functional disabilities. Conclusions Following cerebral ischemia, the phenotype of OPCs in the cerebral cortex shifts from the parenchymal subtype to the perivascular subtype, which can promote angiogenesis. The optimal use of hypoxic OPCs secretome would provide a novel therapeutic option for stroke.