Toll-like receptor 4 (TLR4) is a proinflammatory cascade initiator in poststroke inflammation. In this study, miR-1906, a novel regulator of TLR4, was identified viain silicoanalysis and microRNA profiling in male adult mice and its expression was then quantitated in the ischemic hemisphere. We found miR-1906 to be significantly brain enriched in the ischemic hemisphere and even more drastically enriched in the peri-infarct regions. Furthermore,in vitroexperiments demonstrated that, during oxygen–glucose deprivation, miR-1906 expression was increased in glial cells but decreased in neurons. Surprisingly, despite the augmentation of intracellular abundance, miR-1906 expression in extracellular vesicles was decreased in astrocyte cell culture supernatants, suggesting reduced sources of miR-1906 from glia to neurons. When exogenous miR-1906 was administered, decreased TLR4 protein expression was observed bothin vitroandin vivo. Using Cy3 labeling, exogenous miR-1906 uptake by astrocytes, microglia, and neurons was visualized directlyin vivo. Reduced infarct volumes and improved functional outcomes were observed in middle cerebral artery occlusion mice receiving miR-1906. However, the protective effects of miR-1906 disappeared with the genetic knock-out of TLR4, suggesting that TLR4 is a major target of miR-1906 through which the microRNA exerts its therapeutic effects.SIGNIFICANCE STATEMENTThe current study identified miR-1906 as a novel specific regulator of Toll-like receptor 4 (TLR4) and depicted its distinct expression patterns in different cerebral regions and cell types during ischemic attack. Therefore, the therapeutic supplementation of miR-1906 can be beneficial in the modulation of poststroke inflammation. Using Cy3 labeling, exogenous miR-1906 expression was visualized and shown to enter astrocytes, microglia, and neurons successfullyin vivo. Supplemental therapeutic miR-1906 resulted in reduced TLR4 expression and improved outcomes after middle cerebral artery occlusion in a mouse model, but its neuroprotective function was TLR4 dependent, suggesting that TLR4 is a major target of miR-1906.

INTRODUCTION: Free‐water imaging of the choroid plexus (CP) may improve the evaluation of Alzheimer's disease (AD).METHODS: Our study investigated the role of free‐water fraction (FWf) of CP in AD among 216 participants (133 Aβ+ participants and 83 Aβ– controls) enrolled in the NeuroBank‐Dementia cohort at Ruijin Hospital (RJNB‐D). The Alzheimer's Disease Neuroimaging Initiative dataset was used for external validation.RESULTS: At baseline, Aβ+ participants showed higher CP FWf, increased white matter hyperintensity (WMH) volume, and decreased diffusion tensor image analysis along the perivascular space (DTI‐ALPS). In Aβ+ participants, DTI‐ALPS mediated the association between CP FWf and periventricular WMH. CP FWf was associated with cortical tau accumulation, synaptic loss, hippocampal and cortical atrophy, and cognitive performance. During follow‐up, CP FWf increased faster in Aβ+ participants than controls.DISCUSSION: Elevated CP FWf indicated impaired glymphatic function and AD neurodegeneration, and can be a sensitive biomarker for AD progression. The study was registered on ClinicalTrials.gov (NCT05623124).Highlights: This cohort study found higher free‐water fraction (FWf) of the choroid plexus (CP) in amyloid beta (Aβ)+ participants. CP FWf was related to glymphatic function, brain atrophy, tau burden, synaptic loss, and cognition. Aβ+ participants showed faster growth of CP FWf than Aβ– controls during follow‐up. The growth rate of CP FWf exceeded that of white matter lesion and tau accumulation in Aβ+ participants. CP FWf can serve as a sensitive imaging marker of glymphatic function and Alzheimer's disease progression.

The underlying mechanism of ischemic stroke is not completely known. Regulatory T cells (Tregs), a subset of T cells, play a pivotal role in the pathophysiological process of ischemic stroke. However, there is also controversy over the role of Tregs in stroke. Hence, the function of Tregs in ischemic stroke has triggered a heated discussion recently. In this paper, we reviewed the current lines of evidence to describe the full view of Tregs in stroke. We would like to introduce the basic concepts of Tregs and then discuss their paradox function in ischemic stroke. On one side, Tregs could protect brain against ischemic injury via modulating the inflammation process. On the other side, they exaggerated the insult by causing microvascular dysfunction. They also interfered with the neurological function recovery. In addition, the reasons for this paradox role would be discussed in the review and the prospective of the clinical application of Tregs was also included. In conclusion, Tregs contributed to the outcome of ischemic stroke, while more lines of evidence are needed to understand how Tregs regulate the immune system and influence the outcome of stroke.

Immune system plays an elementary role in the pathophysiological progress of ischemic stroke. It consists of innate and adaptive immune system. Activated within minutes after ischemic onset, innate immunity is responsible for the elimination of necrotic cells and tissue repair, while it is critically involved in the initiation and amplification of poststroke inflammation that amplifies ischemic damage to the brain tissue. Innate immune response requires days to be fully developed, providing a considerable time window for therapeutic intervention, suggesting prospect of novel immunomodulatory therapies against poststroke inflammation-induced brain injury. However, obstacles still exist and a comprehensive understanding of ischemic stroke and innate immune reaction is essential. In this review, we highlighted the current experimental and clinical data depicting the innate immune response following ischemic stroke, mainly focusing on the recognition of damage-associated molecular patterns, activation and recruitment of innate immune cells, and involvement of various cytokines. In addition, clinical trials targeting innate immunity were also documented regardless of the outcome, stressing the requirements for further investigation.

Cortical gray to white matter signal intensity ratio (GWR) measured from T1‐weighted magnetic resonance (MR) images was associated with neurodegeneration and dementia. We characterized topological patterns of GWR during AD pathogenesis and investigated its association with cognitive decline. The study included a cross‐sectional dataset and a longitudinal dataset. The cross‐sectional dataset included 60 cognitively healthy controls, 61 mild cognitive impairment (MCI), and 63 patients with dementia. The longitudinal dataset included 26 participants who progressed from cognitively normal to dementia and 26 controls that remained cognitively normal. GWR was compared across the cross‐sectional groups, adjusted for amyloid PET. The correlation between GWR and cognition performance was also evaluated. The longitudinal dataset was used to investigate GWR alteration during the AD pathogenesis. Dementia with β‐amyloid deposition group exhibited the largest area of increased GWR, followed by MCI with β‐amyloid deposition, MCI without β‐amyloid deposition, and controls. The spatial pattern of GWR‐increased regions was not influenced by β‐amyloid deposits. Correlation between regional GWR alteration and cognitive decline was only detected among individuals with β‐amyloid deposition. GWR showed positive correlation with tau PET in the left supramarginal, lateral occipital gyrus, and right middle frontal cortex. The longitudinal study showed that GWR increased around the fusiform, inferior/superior temporal lobe, and entorhinal cortex in MCI and progressed to larger cortical regions after progression to AD. The spatial pattern of GWR‐increased regions was independent of β‐amyloid deposits but overlapped with tauopathy. The GWR can serve as a promising biomarker of neurodegeneration in AD.