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Background Cooperative defect is 1 of the earliest manifestations of disease patients with Alzheimer disease (AD) exhibit, but the underlying mechanism remains unclear. Methods We evaluated the cooperative function of APP/PS1 transgenic AD model mice at ages 2, 5, and 8 months by using a cooperative drinking task. We examined neuropathologic changes in the medial prefrontal cortex (mPFC). Another experiment was designed to observe whether miconazole, which has a repairing effect on myelin sheath, could promote the cooperative ability of APP/PS1 mice in the early AD-like stage. We also investigated the protective effects of miconazole on cultured mouse cortical oligodendrocytes exposed to human amyloid β peptide (Aβ1-42). Results We observed an age-dependent impairment of cooperative water drinking behavior in APP/PS1 mice. The AD mice with cooperative dysfunction showed decreases in myelin sheath thickness, oligodendrocyte nuclear heterochromatin percentage, and myelin basic protein expression levels in the mPFC. The cooperative ability was significantly improved in APP/PS1 mice treated with miconazole. Miconazole treatment increased oligodendrocyte maturation and myelin sheath thickness without reducing Aβ plaque deposition, reactive gliosis, and inflammatory factor levels in the mPFC. Miconazole also protected cultured oligodendrocytes from the toxicity of Aβ1-42. Conclusions These results demonstrate that mPFC hypomyelination is involved in the cooperative deficits of APP/PS1 mice. Improving myelination through miconazole therapy may offer a potential therapeutic approach for early intervention in AD.

Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive cognitive defects. The role of the central immune dominated by microglia in the progression of AD has been extensively investigated. However, little is known about the peripheral immune system in AD pathogenesis. Recently, with the discovery of the meningeal lymphatic vessels and glymphatic system, the roles of acquired immunity in the maintenance of central homeostasis and neurodegenerative diseases have attracted increasing attention. T cells not only regulate the function of neurons, astrocytes, microglia, oligodendrocytes and brain microvascular endothelial cells, but also participate in clearance of β-amyloid (Aβ) plaques. Apart from producing antibodies to bind Aβ peptides, B cells affect Aβ-related cascades

Patients with autism spectrum disorder (ASD) typically experience substantial social isolation, which may cause secondary adverse effects on their brain development. miR-124 is the most abundant miRNA in the human brain, acting as a pivotal molecule regulating neuronal fate determination. Alterations of miR-124 maturation or expression are observed in various neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. In the present study, we analyzed a panel of brain-enriched microRNAs in serums from 2 to 6 year old boys diagnosed with ASD. The hsa-miR-124 level was found significantly elevated in ASD boys than in age and sex-matched healthy controls. In an isolation-reared weanling mouse model, we evidenced elevated mmu-miR-124 level in the serum and the medial prefrontal cortex (mPFC). These mice displayed significant sociability deficits, as well as myelin abnormality in the mPFC, which was partially rescued by expressing the miR-124 sponge in the bilateral mPFC, ubiquitously or specifically in oligodendroglia. In cultured mouse oligodendrocyte precursor cells, introducing a synthetic mmu-miR-124 inhibited the differentiation process through suppressing expression of nuclear receptor subfamily 4 group A member 1 (Nr4a1). Overexpressing Nr4a1 in the bilateral mPFC also corrected the social behavioral deficits and myelin impairments in the isolation-reared mice. This study revealed an unanticipated role of the miR-124/Nr4a1 signaling in regulating early social experience-dependent mPFC myelination, which may serve as a potential therapy target for social neglect or social isolation-related neuropsychiatric disorders.

Increasing evidence supports the involvement of the peripheral immune system in the pathogenesis of Alzheimer's disease (AD). In the present study, we found that B lymphocytes could mitigate beta-Amyloid (Aβ) pathology and memory impairments in a transgenic AD mouse model. Specifically, in young 5 × FAD mice, we evidenced increased B cells in the frontal cortex and meningeal tissues; depletion of mature B cells aggravated these mice's Aβ load and memory deficits. The increased B cells produced more interleukin-35 (IL-35) in the front cortex. We further found IL-35 neutralization exacerbated Aβ pathology, while injecting IL-35 mitigated Aβ load and cognitive dysfunction in 5 × FAD mice with or without mature B cell deficiency. Mechanistically, IL-35 inhibited neuronal BACE1 transcription through modulating the SOCS1/STAT1 pathway, and reduced Aβ production accordingly. Reanalysis of the single-cell RNA sequencing data from blood samples of AD patients suggested an increased population of IL-35-producing B cells. Together, the present study revealed a novel effect of B lymphocyte-derived IL-35 on inhibiting Aβ production in the frontal cortex, which may serve as a potential target for future AD treatment.

Background and Purpose: Cooperative defect is one of the earliest manifestations of patients with Alzheimer’s disease (AD), but the underlying mechanism remains unclear. The purpose of the current study was to address this issue. Experimental Approach: The cooperative function of APP/PS1 transgenic AD model mice at ages 2, 5 and 8 months was evaluated by a cooperative drinking task. Neuropathological changes were examined in the medial prefrontal cortex (mPFC), a key brain area regulating social behavior. Another experiment was designed to observe whether miconazole, a drug has a protective effect on myelin sheath, could promote cooperative ability of APP/PS1 mice in the early AD-like stage. The protective effects of miconazole on cultured mouse cortical oligodendrocytes exposed to human amyloid β peptide (Aβ1-42) peptide were also investigated. Key Results: There was an age-dependent impairment of cooperative drinking water behavior in APP/PS1 mice. AD mice with cooperative dysfunction showed decreases in myelin sheath thickness, oligodendrocyte nuclear heterochromatin percentage and myelin basic protein expression levels in the mPFC. The cooperative ability was significantly improved in APP/PS1 mice treated with miconazole. Consistently, miconazole increased oligodendrocyte maturation and myelin sheath thickness, without reducing Aβ plaque deposition in the mPFC. Miconazole protected cultured oligodendrocytes from the toxicity of Aβ1-42. Conclusions and Implications: These results demonstrate that mPFC myelin hypomyelination is involved in cooperative deficits of APP/PS1 mice. Improving myelination via miconazole therapy may offer a potential therapeutic approach for early intervention of AD.

Recent progress on the central lymphatic system has greatly increased our understanding of how the brain maintains its own waste homeostasis. Here, we showed that perivascular spaces and meningeal lymphatic vessels form a functional route for clearance of senescent astrocytes from the aging brain. Blocking meningeal lymphatic drainage by ligation of the deep cervical lymph nodes impaired clearance of senescent astrocytes from brain parenchyma, subsequently increasing neuroinflammation in aged mice. By contrast, enhancing meningeal lymphatic vessel diameter by a recombinant adeno-associated virus encoding mouse vascular endothelial growth factor-C (VEGF-C) improved clearance of senescent astrocytes and mitigated neuroinflammation. Mechanistically, VEGF-C was highly expressed in senescent astrocytes, contributing themselves to migrate across lymphatic vessels along C-C motif chemokine ligand 21 (CCL21) gradient by interacting with VEGF receptor 3. Moreover, intra-cisternal injection of antibody against CCL21 hampered senescent astrocytes into the lymphatic vessels and exacerbated short memory defects of aged mice. Together, these findings reveal a new perspective for the meningeal lymphatics in the removal of senescent astrocytes, thus offering a valuable target for therapeutic intervention.

Increasing evidences reveal that the peripheral immune system is involved in the pathogenesis of Alzheimer's disease (AD). Here, we report that pulmonary B lymphocytes mitigate beta-Amyloid (Aβ) pathology in 5xFAD mice. The proportion of B cells, rather than T cells, increases within the brain, meningeal and lung tissues in 3-month-old 5xFAD mice. Deletion of mature B cells aggravates Aβ load and memory deficits of 5xFAD mice. Mechanistically, pulmonary B cells can migrate to the brain parenchyma and produce interleukin-35, which inhibits neuronal β-site APP-cleaving enzyme 1 expression, and subsequently reduces the production of Aβ. In turn, pulmonary B cell proliferation is associated with activation of the toll-like receptor/nuclear factor kappa-B pathway through elevated Aβ that is drained from the brain parenchyma to the lungs via meningeal lymphatics. Furthermore, promoting pulmonary B cell proliferation via overexpression of B-cell-activating factor ameliorates brain Aβ load and improves cognitive functions of 10-month-old 5xFAD mice. Together, these results highlight the lungs as both immune targets and effector organs in Aβ pathogenesis. Pulmonary B cells could serve as a potential target against AD.

Social cooperation is essential to animals’ physical health and psychological state. However, the underlying molecular and neurobiological mechanisms remain poorly understood. Here, we established a novel model for systematically evaluating the cooperative behavior of mice for the task of water reward. Using this paradigm, we characterized cooperative deficits in isolated juvenile mice and the corrective effect of resocialization. Mechanistically, we found that the transcription factor early growth response 2 (Egr2)-dependent myelin maturation in the medial prefrontal cortex is necessary for the development of mice’s cooperative behavior. Additionally, corticosterone levels in the serum and medial prefrontal cortex were elevated in the isolated mice, potentially contributing to Egr2 expression reduction. This work suggests targeting Egr2 could be targeted for preventing and treating social isolation-related neuropsychiatric disorders in the future.

Background: Epidemiological and clinical evidence suggest there is an effective time window for the ability of exercise to slow the progression of Alzheimer's disease (AD). Astrocyte aquaporin-4 (AQP4) dependent glymphatic transport is necessary for clearance of extracellular amyloid-β (Aβ) from the brain. The purpose of this study is to explore whether this Aβ clearance mechanism is involved in the time-dependent benefit of exercise on Aβ related pathology. Method: 3- and 7-month-old male wild type (WT) mice, APP695swe/PS1-dE9 (APP/PS1) mice and AQP4 knockout (AQP4−/−)/APP/PS1 mice received voluntary wheel exercise intervention for 2 months, followed by behavioral and pathological analyses.Results: 9-month-old APP/PS1 mice showed enhanced reactive astrogliosis, accompanied with widespread loss of perivascular AQP4 polarization, when compared to 5-month-old APP/PS1 mice. Voluntary exercise improved AQP4 polarity and glymphatic transport, reduced glial inflammation and brain Aβ plaque load, plus alleviated synapse protein loss and cognitive deficits in 5-month-old, but not 9-month-old, APP/PS1 mice. Exercise intervention did not mitigate glymphatic transport dysfunction, Aβ accumulation and cognitive impairment in AQP4−/−/APP/PS1 mice at 5 or 9 months of age. Conclusion: These results have revealed that AQP4-dependent glymphatic transport is an influential factor in the timeliness of voluntary exercise ability to alleviate Aβ pathology, potentially offering a new target for the early prevention of the disease.

Additional file 1. Morris water maze. The Morris water maze test was conducted to measure mouse long-term spatial cognitive function, as described previously [19]. Four Training was performed over 7 consecutive days, with 4 trials per day. During the first two days, mice were trained to find a dark-colored cylindrical platform with a diameter of 10 cm, sitting 0.5 cm above the water surface. Mice did not receive the next hidden platform tests if they had apparent motor and/or visual deficits indicated by low swimming speed ( 50 s). On the 3rd day, the platform was submerged 1 cm below the surface of the water and moved to the opposite quadrant. Escape latency, swimming distance and swimming speed were calculated. On day 8, the hidden platform was removed, allowing mice to swim freely in the pool for 60 s. The percentage of time spent in the target quadrant and the number of crossing where the platform had been previously located were analyzed. Y-maze test. The Y-maze test was performed to evaluate mouse short-term spatial working memory, as previously described [19]. One arm, termed the novel arm, was blocked by a black baffle, allowing the mice to only move in the other two arms for 5 min. Two hours later, the novel arm was opened, allowing mice to freely move throughout the three arms. The percentage of time traveled in, number of entries into the novel arm, as well as traveling speed during the test, was calculated. Mouse activity in the aforementioned behavioral apparatuses was collected by a digital video camera connected to a computer-controlled system (Beijing Sunny Instruments Co. Ltd., China). All tests were performed by two independent experimenters, who were each blind to the treatment schedule.

Background Abnormal aggregation of brain α-synuclein is a central step in the pathogenesis of Parkinson’s disease (PD), thus, it is reliable to promote the clearance of α-synuclein to prevent and treat PD. Recent studies have revealed an essential role of glymphatic system and meningeal lymphatic vessels in the clearance of brain macromolecules, however, their pathophysiological aspects remain elusive. Method Meningeal lymphatic drainage of 18-week-old A53T mice was blocked via ligating the deep cervical lymph nodes. Six weeks later, glymphatic functions and PD-like phenotypes were systemically analyzed. Results Glymphatic influx of cerebrospinal fluid tracer was reduced in A53T mice, accompanied with perivascular aggregation of α-synuclein and impaired polarization of aquaporin 4 expression in substantia nigra. Cervical lymphatic ligation aggravated glymphatic dysfunction of A53T mice, causing more severe accumulation of α-synuclein, glial activation, inflammation, dopaminergic neuronal loss and motor deficits. Conclusion The results suggest that brain lymphatic clearance dysfunction may be an aggravating factor in PD pathology. Electronic supplementary material The online version of this article (10.1186/s40035-019-0147-y) contains supplementary material, which is available to authorized users.

Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular event that often is followed by permanent brain impairments. It is necessary to explore the pathogenesis of secondary pathological damages in order to find effective interventions for improving the prognosis of SAH. Blockage of brain lymphatic drainage has been shown to worsen cerebral ischemia and edema after acute SAH. However, whether or not there is persistent dysfunction of cerebral lymphatic drainage following SAH remains unclear. In this study, autologous blood was injected into the cisterna magna of mice to establish SAH model. One week after surgery, SAH mice showed decreases in fluorescent tracer drainage to the deep cervical lymph nodes (dcLNs) and influx into the brain parenchyma after injection into the cisterna magna. Moreover, SAH impaired polarization of astrocyte aquaporin-4 (AQP4) that is a functional marker of glymphatic clearance and resulted in accumulations of Tau proteins as well as CD3+, CD4+, and CD8+ cells in the brain. In addition, pathological changes, including microvascular spasm, activation of glial cells, neuroinflammation, and neuronal apoptosis were observed in the hippocampus of SAH mice. Present results demonstrate persistent malfunction of glymphatic and meningeal lymphatic drainage and related neuropathological damages after SAH. Targeting improvement of brain lymphatic clearance potentially serves as a new strategy for the treatment of SAH., Graphical Abstract

The glymphatic system is a brain-wide clearance pathway; its impairment contributes to the accumulation of amyloid-β. Influx of cerebrospinal fluid (CSF) depends upon the expression and perivascular localization of the astroglial water channel aquaporin-4 (AQP4). Prompted by a recent failure to find an effect of Aqp4 knock-out (KO) on CSF and interstitial fluid (ISF) tracer transport, five groups re-examined the importance of AQP4 in glymphatic transport. We concur that CSF influx is higher in wild-type mice than in four different Aqp4 KO lines and in one line that lacks perivascular AQP4 (Snta1 KO). Meta-analysis of all studies demonstrated a significant decrease in tracer transport in KO mice and rats compared to controls. Meta-regression indicated that anesthesia, age, and tracer delivery explain the opposing results. We also report that intrastriatal injections suppress glymphatic function. This validates the role of AQP4 and shows that glymphatic studies must avoid the use of invasive procedures.

The glymphatic pathway and meningeal lymphatic vessels are involved in clearance of metabolic macromolecules from the brain. However, the functional interaction between the two systems in the maintenance of brain homeostasis remains unclear. Here we reported that deletion of aquaporin-4 (AQP4), a functional regulator of glymphatic clearance, aggravated brain pathology of 3 month-old mice after blocking of the meningeal lymphatic drainage for 2 weeks via ligation of the deep cervical lymphatic nodes (LdcLNs). LdcLNs increased total and phosphorylated Tau protein levels in the hippocampus of both genotype mice, but increased hippocampal amyloid beta 1-40 and 1-42 levels only in AQP4 null mice, with up-regulation of beta-site amyloid precursor protein-cleaving enzyme 1 and down-regulation of insulin degrading enzyme. Consistently, LdcLNs caused microglial reactivity and activation of nod-like receptor protein-3 inflammasomes in the AQP4 null hippocampus. These mice also showed hippocampal neuronal apoptosis and declines in exploring and cognitive abilities. Deletion of AQP4, but not LdcLNs, increased brain water content. Together, these findings have revealed respective and interactive roles of the glymphatic system and the dural lymphatic system in maintaining amyloid beta, Tau proteins and water homeostasis in the brain, helping to understand the pathogenesis of neurological diseases associated with mis-accumulation of brain macromolecules.

Value-added tax revenue occupies an important position in China. The efficiency study of value-added tax has important practical significance in the critical point of Chinese value-added tax transformation. Using BCC model we estimate Chinese value-added tax comprehensive efficiency, pure technical efficiency and scale efficiency from 1995 to 2008 from a macro perspective. The study shows that value-added tax maintains a high level of technical efficiency, but scale efficiency still needs to be improved, therefore Chinese value-added tax jurisdiction should be adjust appropriately.