Background: Spontaneous functional recovery occurs during the acute phase after stroke onset, but this intrinsic recovery remains limited. Therefore, exploring the mechanism underlying spontaneous recovery and identifying potential strategies to promote functional rehabilitation after stroke are very important. The CD200/CD200R signaling pathway plays an important role in neurological recovery by modulating synaptic plasticity during multiple brain disorders. However, the effect and mechanism of action of the CD200/CD200R pathway in spontaneous functional recovery after stroke are unclear.Methods: In this study, we used a transient middle cerebral artery occlusion (MCAO) model in rats to investigate the function of CD200/CD200R signaling in spontaneous functional recovery after stroke. We performed a battery of behavioral tests (Longa test, adhesive removal test, limb-use asymmetry test, and the modified grip-traction test) to evaluate sensorimotor function after intracerebroventricular (i.c.v.) injection with CD200 fusion protein (CD200Fc) or CD200R blocking antibody (CD200R Ab) post-stroke. Density and morphology of dendritic spines were analyzed by Golgi staining. Microglia activation was evaluated by immunofluorescence staining. Western blot was used to detect the levels of protein and the levels of mRNA were measured by qPCR. Results: Our study demonstrated that sensorimotor function, synaptic proteins, and structures were gradually recovered and CD200R was transiently upregulated in ipsilateral cortex after stroke. Synapse-related proteins and dendritic spines were preserved, accompanied by sensorimotor functional recovery, after stereotaxic CD200Fc injection post-stroke. In addition, CD200Fc restrained microglia activation and pro-inflammatory factor release (such as Il-1, Tnf-α, and Il-6) after MCAO. On the contrary, CD200R Ab aggravated sensory function recovery in adhesive removal test and further promoted microglia activation and pro-inflammatory factor release (such as Il-1) after MCAO. The immune-modulatory effect of CD200/CD200R signaling might be exerted partly by its inhibition of the MAPK pathway. Conclusions:This study provides evidence that the CD200/CD200R signaling pathway contributes to spontaneous functional recovery by enhancing synaptic plasticity via inhibition of microglia activation and inflammatory factor release.

The disruption of the blood-brain barrier (BBB) plays a critical role in the pathology of ischemic stroke. p75 neurotrophin receptor (p75 NTR ) contributes to the disruption of the blood-retinal barrier in retinal ischemia. However, whether p75 NTR influences the BBB permeability after acute cerebral ischemia remains unknown. The present study investigated the role and underlying mechanism of p75 NTR on BBB integrity in an ischemic stroke mouse model, middle cerebral artery occlusion (MCAO). After 24 h of MCAO, astrocytes and endothelial cells in the infarct-affected brain area upregulated p75 NTR . Genetic p75 NTR knockdown (p75 NTR+/À ) or pharmacological inhibition of p75 NTR using LM11A-31, a selective inhibitor of p75 NTR , both attenuated brain damage and BBB leakage in MCAO mice. Astrocyte-specific conditional knockdown of p75 NTR mediated with an adeno-associated virus significantly ameliorated BBB disruption and brain tissue damage, as well as the neurological functions after stroke. Further molecular biological examinations indicated that astrocytic p75 NTR activated NF-κB and HIF-1α signals, which upregulated the expression of MMP-9 and vascular endothelial growth factor (VEGF), subsequently leading to tight junction degradation after ischemia. As a result, increased leukocyte infiltration and microglia activation exacerbated brain injury after stroke. Overall, our results provide novel insight into the role of astrocytic p75 NTR in BBB disruption after acute cerebral ischemia. The p75 NTR may therefore be a potential therapeutic target for the treatment of ischemic stroke.astrocyte, blood-brain barrier, ischemic stroke, p75 NTR , tight junction proteins | INTRODUCTIONIschemic stroke is a leading cause of mortality and long-term disability worldwide (Matsumoto et al., 2020). It constitutes a major public health burden, yet current therapeutic interventions are limited (Pirson et al., 2020). Thus, there is an urgent need for investigating the mechanism of stroke-induced ischemic injury to find potential pharmacological targets of the disease.Blood-brain barrier (BBB) breakdown is a hallmark of ischemic stroke, which contributes to the brain pathology (Abdullahi et al., 2018;Kassner & Merali, 2015).Therefore, protecting the BBB may be a therapeutic strategy for alleviating brain ischemia injury. The BBB is composed of endothelial cells lining the cerebral vasculature, pericytes, and astrocytic end-feet. The static barrier function of the BBB mainly dependents on endothelial cells and the tight junctions, which restricts paracellular permeability. BBB disruption leads to

Alzheimer's disease (AD) is the most common form of dementia in the elderly (Tanzi, 2012). Mounting evidence suggests that the accumulation and aggregation of amyloidβ (Aβ) are the key initiating event in the pathogenesis of AD (Hardy & Selkoe, 2002). Failure of Aβ clearance or disruption of Aβ homeostasis results in an accumulation of Aβ in the brain. Late-onset AD patients exhibit compromised Aβ clearance rather than overproduction of Aβ; thus, impairment of Aβ clearance is a common antecedent to late-onset AD (Mawuenyega and Sigurdson et al., 2010).Microglia are immune cells that contribute to phagocytosis in the central nervous system, and play critical roles in the uptake of Aβ and dead neural cells (Mandrekar-Colucci & Karlo, 2012). There is an