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Oxidative stress is known to play a critical role in the pathogenesis of various disorders, especially in ischemia/reperfusion (I/R) injury. We identified an apoptosis-inducing humoral factor and named this novel post translationally modified secreted form of eukaryotic translation initiation factor 5A (eIF5A) “oxidative stress-responsive apoptosis inducing protein” (ORAIP). The purpose of this study was to investigate the role of ORAIP in the mechanisms of cerebral I/R injury. Hypoxia/reoxygenation induced expression of ORAIP in cultured rat cerebral neurons, resulting in extensive apoptosis of these cells, which was largely suppressed by neutralizing anti-ORAIP monoclonal antibody (mAb) in vitro . Recombinant-ORAIP induced extensive apoptosis of cerebral neurons. Cerebral I/R induced expression of ORAIP in many neurons in a rat tandem occlusion model in vivo . In addition, we analyzed the effects of intracerebroventricular administration of neutralizing anti-ORAIP mAb on the development of cerebral infarction. Cerebral I/R significantly increased ORAIP levels in cerebrospinal fluid. Treatment with intracerebroventricular administration of neutralizing anti-ORAIP mAb reduced infarct volume by 72%, and by 55% even when started after reperfusion. These data strongly suggest that ORAIP plays a pivotal role and will offer a critical therapeutic target for cerebral I/R injury induced by thrombolysis and thrombectomy for acute ischemic stroke.

The corpus callosum, a major white matter tract in the brain, undergoes age-related functional changes. To extend our investigation of age-related gene expression dynamics in the mouse corpus callosum, we compared RNA-seq data from 2 week-old and 12 week-old wild-type C57BL/6 J mice and identified the differentially expressed genes (e.g., Marcksl1 , Chst3 , C4b , Neat1 , Ndrg1 , Emid1 , etc.) between these ages. Interestingly, we found that genes highly expressed in myelinating oligodendrocytes were upregulated in 12 week-old mice compared to 2 week-old mice, while genes highly expressed in oligodendrocyte precursor cells (OPCs) and newly formed oligodendrocytes were downregulated. Furthermore, by comparing these genes with the datasets from 20 week-old and 96 week-old mice, we identified novel sets of genes with age-dependent variations in the corpus callosum. These gene expression changes potentially affect key biological pathways and may be closely linked to age-related neurological disorders, including dementia and stroke. Therefore, our results provide an additional dataset to explore age-dependent gene expression dynamics of oligodendrocyte lineage cells in the corpus callosum.

Nogo receptor-1 (NgR1) and its ligands inhibit neuronal plasticity and limit functional recovery after brain damage such as ischemic stroke. We have previously shown that lateral olfactory tract usher substance (LOTUS) antagonizes NgR1-mediated signaling. Here, we investigated whether LOTUS enhances neuronal plasticity and functional recovery after brain focal ischemia in adult mice. Focal ischemic infarcts were induced in wild-type and LOTUS-overexpressing transgenic mice via middle cerebral artery occlusion. Endogenous LOTUS expression was increased in brain and cervical spinal cord of the contralateral side of ischemia in the chronic phase after brain ischemia. LOTUS overexpression accelerated midline-crossing axonal sprouting from the contralateral side to the ipsilateral side of ischemia in the medullar reticular formation and gray matter of denervated cervical spinal cord. Importantly, LOTUS overexpression improved neurological score highly correlated with laterality ratio of corticoreticular fibers of the medulla oblongata, indicating that LOTUS overexpression may overcome the inhibitory environment induced by NgR1 signaling for damaged motor pathway reconstruction after ischemic stroke. Thus, our data suggest that LOTUS overexpression accelerates neuronal plasticity in the brainstem and cervical spinal cord after stroke and LOTUS administration is useful for future therapeutic strategies.

β‐amyloid (Aβ) deposits in brain blood vessel walls underlie the vascular pathology of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). Growing evidence has suggested the involvement of cerebrovascular dysfunction in the initiation and progression of cognitive impairment in AD and CAA patients. Therefore, in this study, we assessed the brain vasculome in a mouse model in order to identify cerebrovascular pathways that may be involved in AD and CAA vascular pathogenesis in the context of aging. Brain endothelial cells were isolated from young and old wild‐type mice, and young and old transgenic mice expressing Swedish mutation in amyloid precursor protein and exon 9 deletion in presenilin 1 (APPswe/PSEN1dE9). Microarray profiling of these endothelial transcriptomes demonstrated that accumulation of vascular Aβ in the aging APPswe/PSEN1dE9 mouse is associated with impaired endothelial expression of neurotransmitter receptors and calcium signaling transductors, while the genes involved in cell cycle and inflammation were upregulated. These results suggest that the vascular pathology of AD and CAA may involve the disruption of neurovascular coupling, reactivation of cell cycle in quiescent endothelial cells, and enhanced inflammation. Further dissection of these endothelial mechanisms may offer opportunities to pursue therapies to ameliorate vascular dysfunction in the aging brain of AD and CAA patients. Vascular Aβ accumulation disrupts neurovascular coupling, induces erroneous cell cycle reactivation, and promotes inflammation in cerebral endothelium. These alterations can result in cerebrovascular dysfunction and contribute to the vascular pathology of cerebral amyloid angiopathy and Alzheimer's disease.

The formation of the corpus callosum in the postnatal period is crucial for normal neurological function, and clinical genetic studies have identified an association of 6q24-25 microdeletion in this process. However, the mechanisms underlying corpus callosum formation and its critical gene(s) are not fully understood or identified. In this study, we examined the roles of AKAP12 in postnatal corpus callosum formation by focusing on the development of glial cells, because AKAP12 is coded on 6q25.1 and has recently been shown to play roles in the regulations of glial function. In mice, the levels of AKAP12 expression was confirmed to be larger in the corpus callosum compared to the cortex, and AKAP12 levels decreased with age both in the corpus callosum and cortex regions. In addition, astrocytes expressed AKAP12 in the corpus callosum after birth, but oligodendrocyte precursor cells (OPCs), another major type of glial cell in the developing corpus callosum, did not. Furthermore, compared to wild types, Akap12 knockout mice showed smaller numbers of both astrocytes and OPCs, along with slower development of corpus callosum after birth. These findings suggest that AKAP12 signaling may be required for postnatal glial formation in the corpus callosum through cell- and non-cell autonomous mechanisms.

There are currently no adequate treatments for white-matter injury, which often follows central nervous system maladies and their accompanying neurodegenerative processes. Indeed, the white matter is compromised by the deterioration of the blood-brain barrier and the demyelination of neuronal axons. Key repairs to the white matter are mediated by oligodendrocyte lineage cells after damaging events. Oligodendrocytes are supported by other cells in the neurovascular unit and these cells collaborate in processes such as angiogenesis, neurogenesis, and oligodendrogenesis. Understanding the various interactions between these cells and oligodendrocytes will be imperative for developing reparative therapies for impaired white matter. This minireview will discuss how oligodendrocytes and oligodendrocyte lineage cells mend damage to the white matter and restore brain function ensuing neural injury.

Background Fatigue is a prevalent and debilitating symptom of non-communicable diseases (NCDs); however, its biological basis are not well-defined. This exploratory study aimed to identify key biological drivers of fatigue by integrating metabolomic, microbiome, and genetic data from blood and saliva samples using a multi-omics approach. Methods Metabolomic, microbiome, and single nucleotide polymorphisim analyses were conducted on saliva and blood samples from 52 patients with NCDs. Fatigue dimensions were assessed using the Multidimensional Fatigue Inventory and correlated with biological markers. LightGBM, a gradient boosting algorithm, was used for fatigue prediction, and model performance was evaluated using the F1-score, accuracy, and receiver operating characteristic area under the curve using leave-one-out cross-validation. Statistical analyses included correlation tests and multiple comparison adjustments ( p  < 0.05; false discovery rate <0.05). This study was approved by the Yokohama City University Hospital Ethics Committee (F230100022). Results Plasmalogen synthesis was significantly associated with physical fatigue in both blood and saliva samples. Additionally, homocysteine degradation and catecholamine biosynthesis in the blood were significantly associated with mental fatigue (Holm p  < 0.05). Microbial imbalances, including reduced levels of Firmicutes negativicutes and Patescibacteria saccharimonadia , correlated with general and physical fatigue ( r  = − 0.379, p  = 0.006). Genetic variants in genes, such as GPR180, NOTCH3, SVIL, HSD17B11 , and PLXNA1 , were linked to various fatigue dimensions (r range: −0.539–0.517, p  < 0.05). Machine learning models based on blood and salivary biomarkers achieved an F1-score of approximately 0.7 in predicting fatigue dimensions. Conclusion This study provides preliminary insights into the potential involvement of alterations in lipid metabolism, catecholamine biosynthesis disruptions, microbial imbalances, and specific genetic variants in fatigue in patients with NCDs. These findings lay the groundwork for personalized interventions, although further validation and model refinement across diverse populations are needed to enhance the prediction performance and clinical applicability.

BackgroundEndovascular embolization using standalone coils is the preferred treatment option for ruptured cerebral aneurysms to avoid the use of dual antiplatelet therapy with stent coiling or endoluminal flow diversion devices. However, it has been reported that patients undergoing the standalone coiling approach are at risk for periprocedural thromboembolism. Therefore, this systematic review and meta-analysis was performed to clarify the risks and benefits of antiplatelet therapy (AT) during coiling procedures performed to treat ruptured aneurysms, including the incidence of early thromboembolic events, hemorrhagic and delayed ischemic events, as well as clinical outcomes.MethodsA comprehensive search of three databases was performed for articles from inception to June 2021. After fulfilling the inclusion criteria, five studies were included in this meta-analysis and 462 patients with aneurysmal subarachnoid hemorrhage (aSAH) were identified who underwent endovascular standalone coiling treatment. Aneurysm location, patient characteristics, and aSAH grades were comparable between the AT and non-AT groups.ResultsAT significantly decreased the incidence of thromboembolic events immediately after the coiling procedures compared with non-AT (OR 3.42; 95% CI 1.77 to 6.61, p<0.001). The incidences of hemorrhage, delayed ischemia, and clinical outcomes with or without AT were not significantly different between groups.ConclusionsAlthough this study showed no beneficial effect of AT on clinical outcomes, the results suggest that AT could be combined with standalone coiling to avoid thromboembolism during the perioperative period. A large prospective study and/or an additional meta-analysis would be required to further investigate how AT benefits standalone coil embolization in aSAH.

A-kinase anchor protein 12 (AKAP12) is a scaffolding protein that associates with intracellular molecules to regulate multiple signal transductions. Although the roles of AKAP12 in the central nervous system are still relatively understudied, it was previously shown that AKAP12 regulates blood-retinal barrier formation. In this study, we asked whether AKAP12 also supports the function and integrity of the blood-brain barrier (BBB). In a mouse model of focal ischemia, the expression level of AKAP12 in cerebral endothelial cells was upregulated during the acute phase of stroke. Also, in cultured cerebral endothelial cells, oxygen-glucose deprivation induced the upregulation of AKAP12. When AKAP12 expression was suppressed by an siRNA approach in cultured endothelial cells, endothelial permeability was increased along with the dysregulation of ZO-1/Claudin 5 expression. In addition, the loss of AKAP12 expression caused an upregulation/activation of the Rho kinase pathway, and treatment of Rho kinase inhibitor Y-27632 mitigated the increase of endothelial permeability in AKAP12-deficient endothelial cell cultures. These in vitro findings were confirmed by our in vivo experiments using Akap12 knockout mice. Compared to wild-type mice, Akap12 knockout mice showed a larger extent of BBB damage after stroke. However, the inhibition of rho kinase by Y-27632 tightened the BBB in Akap12 knockout mice. These data may suggest that endogenous AKAP12 works to alleviate the damage and dysfunction of the BBB caused by ischemic stress. Therefore, the AKAP12-rho-kinase signaling pathway represents a novel therapeutic target for stroke.

Clinical evidence suggests that patients with subcortical ischemic vascular dementia (SIVD) perform better at cognitive tests after exercise. However, the underlying mechanism for this effect is largely unknown. Here, we examined how treadmill exercise changes the cognitive function and white matter cellular pathology in a mouse model of SIVD. Prolonged cerebral hypoperfusion was induced in 2-month-old male C57BL/6J mice by bilateral common carotid artery stenosis. A week later, the mice were randomly divided into a group that received 6-week treadmill exercise and a sedentary group for observation. In multiple behavioral tests (Y-maze, novel object recognition, and Morris water maze tests), the treadmill exercise training was shown to ameliorate cognitive decline in the hypoperfused SIVD mice. In addition, immunohistological analyses confirmed that there was a larger population of oligodendrocyte precursor cells in the subventricular zone of exercised versus sedentary mice. Although further investigations are needed to confirm a causal link between these findings, our study establishes a model and cellular foundation for investigating the mechanisms through which exercise preserves cognitive function in SIVD.