A roadmap for research in post-stroke fatigue: Consensus-based core recommendations from the third Stroke Recovery and Rehabilitation Roundtable.

Rationale: Fatigue affects almost half of all people living with stroke. Stroke survivors rank understanding fatigue and how to reduce it as one of the highest research priorities.

Methods: We convened an interdisciplinary, international group of clinical and pre-clinical researchers and lived experience experts.

Regulation of the hippocampal translatome by Apoer2-ICD release.

Background: ApoE4, the most significant genetic risk factor for late-onset Alzheimer's disease (AD), sequesters a pro-synaptogenic Reelin receptor, Apoer2, in the endosomal compartment and prevents its normal recycling. In the adult brain, Reelin potentiates excitatory synapses and thereby protects against amyloid-β toxicity. Recently, a gain-of-function mutation in Reelin that is protective against early-onset AD has been described.

Apoer2-ICD-dependent regulation of hippocampal ribosome mRNA loading.

ApoE4, the most significant genetic risk factor for late-onset Alzheimer's disease (AD), sequesters a pro-synaptogenic Reelin receptor, Apoer2, in the endosomal compartment and prevents its normal recycling. In the adult brain, Reelin potentiates excitatory synapses and thereby protects against amyloid-β toxicity. Recently, a gain-of-function mutation in Reelin that is protective against early-onset AD has been described.

A roadmap for research in post-stroke fatigue: Consensus-based core recommendations from the third Stroke Recovery and Rehabilitation Roundtable.

Rationale: Fatigue affects almost half of all people living with stroke. Stroke survivors rank understanding fatigue and how to reduce it as one of the highest research priorities.

Methods: We convened an interdisciplinary, international group of clinical and pre-clinical researchers and lived experience experts.

Brain-associated innate leukocytes display diverse inflammatory states following experimental stroke.

Previous studies investigating innate leukocyte recruitment into the brain after cerebral ischemia have shown conflicting results. Using distinct cell surface and intracellular markers, the current study evaluated the contributions of innate immune cells to the poststroke brain following 1-h middle cerebral artery occlusion (tMCAO) or permanent MCAO (pMCAO), and assessed whether these cells ascribed to an inflammatory state. Moreover, we examined whether there is evidence for leukocyte infiltration into the contralateral (CL) hemisphere despite the absence of stroke infarct.

NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load.

Apolipoprotein E4 (ApoE4) is the most important and prevalent risk factor for late-onset Alzheimer's disease (AD). The isoelectric point of ApoE4 matches the pH of the early endosome (EE), causing its delayed dissociation from ApoE receptors and hence impaired endolysosomal trafficking, disruption of synaptic homeostasis, and reduced amyloid clearance. We have shown that enhancing endosomal acidification by inhibiting the EE-specific sodium-hydrogen exchanger 6 (NHE6) restores vesicular trafficking and normalizes synaptic homeostasis.

Reelin Regulates Neuronal Excitability through Striatal-Enriched Protein Tyrosine Phosphatase (STEP) and Calcium Permeable AMPARs in an NMDAR-Dependent Manner.

Alzheimer's disease (AD) is a progressive neurodegenerative disease marked by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles. Aβ oligomers cause synaptic dysfunction early in AD by enhancing long-term depression (LTD; a paradigm for forgetfulness) via metabotropic glutamate receptor (mGluR)-dependent regulation of striatal-enriched tyrosine phosphatase (STEP). Reelin is a neuromodulator that signals through ApoE (apolipoprotein E) receptors to protect the synapse against Aβ toxicity (Durakoglugil et al.

Dynamic roles of neutrophils in post-stroke neuroinflammation.

Clinical trials involving the blockage of peripheral inflammatory leukocyte recruitment into the brain have puzzlingly led to either no significant improvement in stroke outcome, or even worsened outcomes and increased mortality, prompting a re-evaluation of our understanding into the neuroinflammatory processes after stroke. Whilst traditionally understood as simple effectors of the innate immune system, emerging research in vascular disease biology has redefined the neutrophil as a specialized and highly specific cell type with dynamic functional capacity. Indeed, emerging experimental evidence indicates that neutrophils display diverse roles in the acute stages of ischemic stroke with the ability to elicit both pro-inflammatory and anti-inflammatory effects.

Imbalance in the force: the dark side of the microbiota on stroke risk and progression.

The composition of the gut microbiota depends on many factors, including our lifestyle, diet, metabolism, antibiotic use and hygiene. The contribution of these factors in shaping the gut microbiota and the subsequent effects on the prevention and development of stroke has been under intense investigation. Furthermore, several reports have uncovered the impact of stroke on intestinal dysfunction and gut dysbiosis, highlighting the delicate interplay between the brain, gut and microbiome following this acute brain injury.

Targeting tauopathy with engineered tau-degrading intrabodies.

Background: The accumulation of pathological tau is the main component of neurofibrillary tangles and other tau aggregates in several neurodegenerative diseases, referred to as tauopathies. Recently, immunotherapeutic approaches targeting tau have been demonstrated to be beneficial in decreasing tauopathy in animal models. We previously found that passive immunotherapy with anti-tau antibody to human tau or expression of an anti-tau secreted single-chain variable fragment (scFv) in the central nervous system of a mouse model of tauopathy decreased but did not remove all tau-associated pathology.

Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer's disease.

ApoE4 genotype is the most prevalent and also clinically most important risk factor for late-onset Alzheimer's disease (AD). Available evidence suggests that the root cause for this increased risk is a trafficking defect at the level of the early endosome. ApoE4 differs from the most common ApoE3 isoform by a single amino acid that increases its isoelectric point and promotes unfolding of ApoE4 upon endosomal vesicle acidification.

IL-33 modulates inflammatory brain injury but exacerbates systemic immunosuppression following ischemic stroke.

Stroke triggers a complex inflammatory process in which the balance between pro- and antiinflammatory mediators is critical for the development of the brain infarct. However, systemic changes may also occur in parallel with brain inflammation. Here we demonstrate that administration of recombinant IL-33, a recently described member of the IL-1 superfamily of cytokines, promotes Th2-type effects following focal ischemic stroke, resulting in increased plasma levels of Th2-type cytokines and fewer proinflammatory (3-nitrotyrosine+F4/80+) microglia/macrophages in the brain.

AAV-mediated expression of anti-tau scFvs decreases tau accumulation in a mouse model of tauopathy.

Tauopathies are characterized by the progressive accumulation of hyperphosphorylated, aggregated forms of tau. Our laboratory has previously demonstrated that passive immunization with an anti-tau antibody, HJ8.5, decreased accumulation of pathological tau in a human P301S tau-expressing transgenic (P301S-tg) mouse model of frontotemporal dementia/tauopathy.

Prolonged Activation of Invariant Natural Killer T Cells and T2-Skewed Immunity in Stroke Patients.

Background: Infection is highly prevalent and contribute significantly to mortality of stroke patients. In addition to the well described robust systemic lymphocytopenia and skewed T helper 2 (T2)-immunity after stroke, emerging experimental evidence demonstrate that the development of infection poststroke is attributed by the activation of invariant natural killer T (NKT) cells. In this prospective study, we examined the levels of a broad spectrum of inflammatory mediators, the activation status of NKT cell in the blood of patients with various degree of stroke severity, and investigate whether these parameters differ in patients who later develop poststroke infections.

Translocation and dissemination of commensal bacteria in post-stroke infection.

Bacterial infection is highly prevalent in patients who have had a stroke. Despite the potential contribution of micro-aspiration in post-stroke pneumonia, we found that the majority of the microorganisms detected in the patients who developed infections after having a stroke were common commensal bacteria that normally reside in the intestinal tracts. In a mouse model of ischemic stroke, post-stroke infection was only observed in mice that were born and raised in specific-pathogen-free facilities; this was not seen in mice that were born and raised in germ-free facilities.

G Protein-Coupled Receptor 43 Modulates Neutrophil Recruitment during Acute Inflammation.

Fermentation of dietary fibre in the gut yields large amounts of short chain fatty acids (SCFAs). SCFAs can impart biological responses in cells through their engagement of 'metabolite-sensing' G protein-coupled receptors (GPCRs). One of the main SCFA receptors, GPR43, is highly expressed by neutrophils, which suggests that the actions of GPR43 and dietary fibre intake may affect neutrophil recruitment during inflammatory responses in vivo.

Avenues to autoimmune arthritis triggered by diverse remote inflammatory challenges.

Environmental factors contribute to development of autoimmune diseases. For instance, human autoimmune arthritis can associate with intestinal inflammation, cigarette smoking, periodontal disease, and various infections. The cellular and, molecular pathways whereby such remote challenges might precipitate arthritis or flares remain unclear.

CRIg Functions as a Macrophage Pattern Recognition Receptor to Directly Bind and Capture Blood-Borne Gram-Positive Bacteria.

Kupffer cells (KCs), the vast pool of intravascular macrophages in the liver, help to clear blood-borne pathogens. The mechanisms by which KCs capture circulating pathogens remain unknown. Here we use intra-vital imaging of mice infected with Staphylococcus aureus to directly visualize the dynamic process of bacterial capture in the liver.

Protective actions of des-acylated ghrelin on brain injury and blood-brain barrier disruption after stroke in mice.

The major ghrelin forms, acylated ghrelin and des-acylated ghrelin, are novel gastrointestinal hormones. Moreover, emerging evidence indicates that these peptides may have other functions including neuro- and vaso-protection. Here, we investigated whether post-stroke treatment with acylated ghrelin or des-acylated ghrelin could improve functional and histological endpoints of stroke outcome in mice after transient middle cerebral artery occlusion (tMCAo).

Bugging inflammation: role of the gut microbiota.

The advent of vaccination and improved hygiene have eliminated many of the deadly infectious pathogens in developed nations. However, the incidences of inflammatory diseases, such as inflammatory bowel disease, asthma, obesity and diabetes are increasing dramatically. Research in the recent decades revealed that it is indeed the lack of early childhood microbial exposure, increase use of antibiotics, as well as increase consumption of processed foods high in carbohydrates and fats, and lacking fibre, which wreak havoc on the proper development of immunity and predispose the host to elevated inflammatory conditions.

Ischemia, Immunosuppression and Infection--Tackling the Predicaments of Post-Stroke Complications.

The incidence of stroke has risen over the past decade and will continue to be one of the leading causes of death and disability worldwide. While a large portion of immediate death following stroke is due to cerebral infarction and neurological complications, the most common medical complication in stroke patients is infection. In fact, infections, such as pneumonia and urinary tract infections, greatly worsen the clinical outcome of stroke patients.

The Role of Follicular Helper T Cell Molecules and Environmental Influences in Autoantibody Production and Progression to Inflammatory Arthritis in Mice.

Objective: Antibody-mediated autoimmunity involves cognate interactions between self-reactive T cells and B cells during germinal center (GC) reactions. The aim of this study was to determine the role of essential follicular helper T (Tfh) cell molecules (CXCR5, signaling lymphocytic activation molecule-associated protein) on autoreactive CD4+ cells and the role of certain environmental influences that may determine GC-driven autoantibody production and arthritis development.

Methods: We transferred self-reactive CD4+ cells from KRN-Tg mice into recipient mice, which induced autoantibodies and autoinflammatory arthritis.

Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites.

Asthma is prevalent in Western countries, and recent explanations have evoked the actions of the gut microbiota. Here we show that feeding mice a high-fibre diet yields a distinctive gut microbiota, which increases the levels of the short-chain fatty acid, acetate. High-fibre or acetate-feeding led to marked suppression of allergic airways disease (AAD, a model for human asthma), by enhancing T-regulatory cell numbers and function.