SARS-CoV-2 spike S1 protein induces microglial NLRP3-dependent neuroinflammation and cognitive impairment in mice.

Cognitive impairment is often found at the acute stages and sequelae of coronavirus disease 2019 (COVID-19), and the underlying mechanisms remain unclear. The S1 protein from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be a cause of cognitive impairment associated with COVID-19. The nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome and neuroinflammation play important roles in Alzheimer's disease (AD) with cognitive impairment.

Expression of human Ras-related protein Rab39B variant T168K in leads to motor dysfunction and dopaminergic neuron degeneration.

Human RAB39B gene is related to familial early-onset Parkinson disease. In early adulthood, men with the RAB39B c.503C > A (Thr168Lys, p.

Phosphorylation of AQP4 by LRRK2 R1441G impairs glymphatic clearance of IFNγ and aggravates dopaminergic neurodegeneration.

Aquaporin-4 (AQP4) is essential for normal functioning of the brain's glymphatic system. Impaired glymphatic function is associated with neuroinflammation. Recent clinical evidence suggests the involvement of glymphatic dysfunction in LRRK2-associated Parkinson's disease (PD); however, the precise mechanism remains unclear.

Cortical microinfarcts potentiate recurrent ischemic injury through NLRP3-dependent trained immunity.

Microinfarcts are common among the elderly and patients with microinfarcts are more vulnerable to another stroke. However, the impact of microinfarcts on recurrent stroke has yet to be fully understood. The purpose of this study was to explore the negative effects of microinfarcts on recurrent stroke.

Exogenous monocyte myeloid-derived suppressor cells ameliorate immune imbalance, neuroinflammation and cognitive impairment in 5xFAD mice infected with Porphyromonas gingivalis.

Background: Periodontitis is closely associated with the pathogenesis of Alzheimer's disease (AD). Porphyromonas gingivalis (Pg), the keystone periodontal pathogen, has been reported in our recent study to cause immune-overreaction and induce cognitive impairment. Monocytic myeloid-derived suppressor cells (mMDSCs) possess potent immunosuppressive function.

Mutant VPS35-D620N induces motor dysfunction and impairs DAT-mediated dopamine recycling pathway.

The D620N mutation in vacuolar protein sorting protein 35 (VPS35) gene has been identified to be linked to late onset familial Parkinson disease (PD). However, the pathophysiological roles of VPS35-D620N in PD remain unclear. Here, we generated the transgenic Caenorhabditis elegans overexpressing either human wild type or PD-linked mutant VPS35-D620N in neurons.

-Induced Cognitive Impairment Is Associated With Gut Dysbiosis, Neuroinflammation, and Glymphatic Dysfunction.

Background: Periodontal pathogen and gut microbiota are closely associated with the pathogenesis of Alzheimer's disease (AD). (Pg), the keystone periodontal pathogen, can induce cognitive impairment. The gut has a connection and communication with the brain, which is an important aspect of the gut-brain axis (GBA).

Overexpression of Slit2 decreases neuronal excitotoxicity, accelerates glymphatic clearance, and improves cognition in a multiple microinfarcts model.

Background: Cerebral microinfarcts (MIs) lead to progressive cognitive impairments in the elderly, and there is currently no effective preventative strategy due to uncertainty about the underlying pathogenic mechanisms. One possibility is the dysfunction of GABAergic transmission and ensuing excitotoxicity. Dysfunction of GABAergic transmission induces excitotoxicity, which contributes to stroke pathology, but the mechanism has kept unknown.

hUCMSCs Mitigate LPS-Induced Trained Immunity in Ischemic Stroke.

Innate immune memory is a part of the innate immune system that facilitates the elimination of pathogens. However, it may exacerbate neuropathology. In this study, we found that innate immune memory is detrimental in stroke, because it promotes the acute immune response and exacerbates ischemic infarcts.

Mettl5 mediated 18S rRNA N6-methyladenosine (mA) modification controls stem cell fate determination and neural function.

Ribosome RNA (rRNA) accounts for more than 80% of the cell's total RNA, while the physiological functions of rRNA modifications are poorly understood. Mutations of 18S rRNA mA methyltransferase METTL5 cause intellectual disability, microcephaly, and facial dysmorphisms in patients, however, little is known about the underlying mechanisms. In this study, we identified METTL5 protein complex and revealed that METTL5 mainly interacts with RNA binding proteins and ribosome proteins.

Continuous theta burst stimulation dilates meningeal lymphatic vessels by up-regulating VEGF-C in meninges.

Background: Lymphatic vessels (LVs) of meninges and lymphatic drainage in the brain have been investigated previously. Here, we examined the role of continuous theta burst stimulation (CTBS) in the modulation of meningeal LVs.

Methods: To explore the effects of CTBS on meningeal LVs, the diameters of LVs were measured between a real CTBS group and sham CTBS group of wild-type male mice.

Rational Design of Cyclometalated Iridium(III) Complexes for Three-Photon Phosphorescence Bioimaging.

Compared to 2PE (two-photon excitation) microscopy, 3PE microscopy has superior spatial resolution, deeper tissue penetration, and less defocused interference. The design of suitable agents with a large Stokes shift, good three-photon absorption (3PA), subcellular targeting, and fluorescence lifetime imaging (FLIM) properties, is challenging. Now, two Ir complexes (3PAIr1 and 3PAIr2) were developed as efficient three-photon phosphorescence (3PP) agents.

Mutations of are responsible for sporadic cerebral cavernous malformation and lead to a mulberry-like cluster in zebrafish.

Although familial forms of cerebral cavernous malformation are mainly attributed to three genes (, and ), no mutation is identified in sporadic cerebral cavernous malformation cases with a unique lesion, indicating additional genes for sporadic cerebral cavernous malformation. To screen the candidate genes, we conducted whole exome sequencing in 31 sporadic cerebral cavernous malformation patients and 32 healthy controls, and identified 5 affected individuals carrying 6 heterozygous deleterious mutations in but no mutation in healthy individuals. To further confirm was associated with cerebral cavernous malformation, we generated homozygous knockout zebrafish and found mutation of in zebrafish led to a mulberry-like cluster of disordered-flow vascular channels which was reminiscent of human cerebral cavernous malformation.

Phasic GABA signaling mediates the protective effects of cTBS against cerebral ischemia in mice.

Continuous theta burst stimulation (cTBS) has been widely recognized as a therapeutic treatment for ischemic stroke, but the underlying mechanism is still elusive. Here, we investigated the protective effects of cTBS in the posterior parietal cortex during the chronic phase of stroke in the photothrombotic ischemic model. Infarction volume and neuron excitability in the peri-infarct area were assessed using immunohistochemistry and whole-cell patch-clamp.

Mesenchymal stem cells alleviate AQP-4-dependent glymphatic dysfunction and improve brain distribution of antisense oligonucleotides in BACHD mice.

Huntington's disease (HD) is a neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene that results in the production of neurotoxic mutant HTT (mHTT) protein. Suppressing HTT production with antisense oligonucleotides (ASOs) is a promising treatment strategy for HD; however, the difficulty of delivering ASOs to deep brain structures is a major barrier for its clinical application. The glymphatic system of astrocytes involving aquaporin 4 (AQP-4) controls the entry of macromolecules from the cerebrospinal fluid into the brain.

Continuous theta burst stimulation provides neuroprotection by accelerating local cerebral blood flow and inhibiting inflammation in a mouse model of acute ischemic stroke.

Acute ischemic stroke is a leading cause of disability with limited therapeutic options. Continuous theta burst stimulation (cTBS) has recently been shown to be a promising noninvasive therapeutic strategy for neuroprotection in ischemic stroke patients. Here, we investigated the protective effects of cTBS following acute infarction using a photothrombotic stroke (PTS) model in the right posterior parietal cortex (PPC) of C57BL/6 mice.

Extracellular ASC exacerbated the recurrent ischemic stroke in an NLRP3-dependent manner.

Using a photothrombotic mouse model of single stroke, we show that a single stroke onset increases the nuclear factor-κB (NF-κB), NLR family CARD domain containing protein 4 (NLRC4), and absent in melanoma 2 (AIM2) inflammasomes, as well as the mRNA levels of NLRP3. Next, using a photothrombotic mouse model of recurrent stroke, we found that recurrent strokes increased the activation of NLRP3, exacerbated the brain damage and the pro-inflammatory response in wild type (WT) mice, but not in NLRP3 knockout ( KO) mice. Additionally, we found that apoptosis-associated speck-like protein containing a CARD (ASC) protein level surrounding the infarct area was comparatively increased, but that ASC specks outside of microglia in both the ipsilateral and contralateral of stroke site were decreased in KO mice relative to wild-type (WT) controls, and the number of ASC specks surrounding the second infarct area was positively correlated to the damage scores.

Increased cortical infarction and neuroinflammation in ischemic stroke mice with experimental periodontitis.

Ischemic stroke is a common life-threatening disease. Epidemiological studies have shown that chronic periodontitis is closely related to ischemic stroke. However, it remains unknown whether periodontitis plays a direct role in the injury of cerebral ischemia.

Xyloketal derivative C53N protects against mild traumatic brain injury in mice.

Purpose: Mild traumatic brain injury (mTBI), the most common type of TBI, can result in prolonged cognitive impairment, mood disorders, and behavioral problems. Reducing oxidative stress and inflammation can rescue the neurons from mTBI-induced cell death. Xyloketal B, a natural product from mangrove fungus, has shown good antioxidative and neuroprotective effects in several disease models.

Evaluation of neuroactive effects of ethanol extract of Schisandra chinensis, Schisandrin, and Schisandrin B and determination of underlying mechanisms by zebrafish behavioral profiling.

Schisandra chinensis, a traditional Chinese medicine (TCM), has been used to treat sleep disorders. Zebrafish sleep/wake behavioral profiling provides a high-throughput platform to screen chemicals, but has never been used to study extracts and components from TCM. In the present study, the ethanol extract of Schisandra chinensis and its two main lignin components, schisandrin and schisandrin B, were studied in zebrafish.

Chronic colitis induces meninges traffic of gut-derived T cells, unbalances M1 and M2 microglia/macrophage and increases ischemic brain injury in mice.

Ischemic stroke is one of the most common diseases leading to death and is the primary cause of physical handicap. Recent studies have reported that chronic colitis increases the risk of ischemic stroke, but it is unknown whether chronic colitis participates in ischemic brain injury directly. A combined mouse model of chronic colitis induced by dextran sodium sulfate (DSS) and ischemic stroke induced by photochemical infarction was used in this study.

Vagus Nerve Stimulation Attenuates Cerebral Microinfarct and Colitis-induced Cerebral Microinfarct Aggravation in Mice.

Cerebral cortical microinfarct (CMI) is common in patients with dementia and cognitive decline. Emerging studies reported that intestinal dysfunction influenced the outcome of ischemic stroke and that vagus nerve stimulation (VNS) protected against ischemic stroke. However, the effects of intestinal dysfunction and VNS on CMI are not clear.

Effects of Voluntary Wheel-Running Types on Hippocampal Neurogenesis and Spatial Cognition in Middle-Aged Mice.

While increasing evidence demonstrated that voluntary wheel running promotes cognitive function, little is known on how different types of voluntary wheel running affect cognitive function in elderly populations. We investigated the effects of various voluntary wheel-running types on adult hippocampal neurogenesis and spatial cognition in middle-aged mice. Male C57BL6 and Thy1-green fluorescent protein (GFP) transgenic mice (13 months) were equally assigned to one of the following groups: (1) T1: no voluntary wheel running; (2) T2: intermittent voluntary wheel running; and (3) T3: continuous voluntary wheel running.

Enriched Brain Omega-3 Polyunsaturated Fatty Acids Confer Neuroprotection against Microinfarction.

Cerebral microinfarcts have significant effects on the development of geriatric neurological disorders, including vascular dementia and Alzheimer's disease. However, little is known about the pathophysiological mechanisms involved in the evolution of microinfarcts and potential treatment and prevention against these microvascular ischemic lesions. In the present study, the "single cortical microinfarct model" generated via occluding a penetrating arteriole by femtosecond laser ablation and the "multiple diffuse microinfarcts model" induced by unilateral injection of cholesterol crystals through the internal carotid artery were established to investigate the pathophysiological mechanisms underlying the evolution of microinfarcts and the effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) on alleviating microinfarct burdens and functional deficits.