NeuroImmunology

Meningeal lymphatic dysfunction promotes amyloid-β deposition in the meninges and worsens brain amyloid-β pathology, acting as an aggravating factor in Alzheimer’s disease and in age-associated cognitive decline; improving meningeal lymphatic function could help to prevent or delay age-associated neurological diseases.

T cells continuously sample CNS-derived antigens in the periphery, yet it is unknown how they sample and respond to CNS antigens derived from distinct brain areas. We expressed ovalbumin (OVA) neoepitopes in regionally distinct CNS areas (Cnp-OVA and Nes-OVA mice) to test peripheral antigen...

In this study, a tolerogenic artificial APC (TaAPC) was developed to directly and selectively modulate myelin-autoreactive CD4+ and CD8+ T cells in the myelin oligodendrocyte glycoprotein (MOG)35–55 peptide–induced experimental autoimmune encephalomyelitis in C57BL/6J mice.

17 Jul 2018 Remember those eerie research findings evoking “The Twilight Zone”? Mysterious ingredients in the blood of young mice rejuvenated the brains of their elders, while the blood of old mice sped up aging in young’uns. The identity of blood-borne agents of aging remains a mystery, but researchers believe they have at least zeroed in on the agents’ gateway to the brain. At the joint Keystone symposia Advances in Neurodegenerative Disease Research and Therapy / New Frontiers in Neuroinflammation, held June 17–21 in Keystone, Colorado, Tony Wyss-Coray of Stanford University in Palo Alto reported that expression of vascular cell adhesion molecule 1 (VCAM1) on brain endothelial cells was required for old blood to accelerate aging in young brains. In fact, blocking this receptor even slowed classic symptoms of normal brain aging, such as less neurogenesis and more neuroinflammation, in control mice that never received blood transfusions. VCAM1 expression on the luminal side of blood endothelial cells rises with age. VCAM1 expression on the luminal side of blood endothelial cells rises with age. Only with VCAM1 did blood from old mice speed up aging in the brains of young mice. Blood from active mice boosted neurogenesis in sedentary ones. Alkahest started a Phase 2 trial testing a fraction from young human plasma in people with AD. The findings cement the role of systemic factors in brain aging and suggest that blocking their lines of communication with the brain could have restorative effects. The therapeutic prospect is especially appealing because treatments targeting VCAM1 would not need to cross the blood-brain barrier, which remains a formidable hurdle for CNS drug development. The researchers uploaded their findings to BioRxiv, where the pdf has been viewed nearly 2,200 times since January (Yousef et al., 2018).  Aging is the strongest risk factor for Alzheimer’s and most other neurodegenerative diseases. Circulating factors play a key role, according to findings over the years by Wyss-Coray and colleagues. Not only did they find that blood from young mice halted synaptic deficits, loss of neurogenesis, and even memory loss in AD mouse models, but blood from old mice quickened these processes in young mice (Aug 2011 news; May 2014 conference news; Sep 2016 conference news).  At Keystone, Wyss-Coray presented new results of efforts to understand how outside factors manage to drive aging inside the brain. Reasoning that the blood-brain barrier must be an active participant, Wyss-Coray and colleagues sifted through plasma proteomics data the lab had generated in years prior. They searched for proteins whose concentration shot up with age, and which were known to be expressed by the brain endothelial cells (BECs) that line the BBB. Of the 31 proteins that went up with age, eight were expressed in BECs, and five of those were implicated in vascular function. Of those five, soluble VCAM1 stood out as the protein that increased most in the plasma with age, Wyss-Coray reported at Keystone.  VCAM1 Opens Door to Aging. In the young brain, low levels of VCAM1 on brain endothelial cells allow microglia to remain ramified and calm, and neurogenesis to proceed. In the old brain, these cells increase VCAM1 expression, which tethers more leukocytes to their luminal side. This activates microglia, suppresses neurogenesis. [Courtesy of Yousef et al., BioRxiv, 2018.] VCAM1 is part of the immunoglobulin receptor family, whose expression rises on many cell types in response to injury. The receptor binds to the integrin VLA4, expressed on leukocytes. The soluble version of VCAM1—sVCAM1—is continually shed by the ADAM17 protease, and its concentration in the blood correlates with cognitive impairment and even mortality, Wyss-Coray said. To investigate VCAM1 expression on BECs, the scientists infused fluorescently tagged anti-VCAM1 antibodies into mice; this labeled cells expressing the receptor on the luminal side of the cerebrovasculature. They found a patchy, sparse expression pattern. In young mice, at most 4 percent of BECs in hippocampal blood vessels expressed VCAM1, and this rose to about 5 percent as the animals aged. Injecting young mice with lipopolysaccharide boosted VCAM1 expression to 15 percent of BECs, and even more so in older mice. Single-cell RNA sequencing of BECs revealed that VCAM1 expression was limited to BECs in arteries/arterioles and veins/venules; it was not expressed in capillaries. A single-cell transcriptomic study of the brain vasculature, by Christer Betsholtz at Sweden’s Uppsala University, also reported expression of VCAM1 on arteries and veins, but not capillaries (Vanlandewijck et al., 2018).  At Keystone, Wyss-Coray reported that vein/venule BECs expressing VCAM1 also expressed a slew of pro-inflammatory cytokine receptor genes, as well as receptors known to interact with leukocytes. The researchers next investigated how young versus old plasma affected BEC VCAM1 expression. Exposing young mice to plasma from aged mice—whether via parabiosis or intravenous injection—boosted VCAM1 expression on BECs. Similarly, cultured BECs ramped up VCAM1 expression when treated with plasma from old, but not young, mice. Notably, the researchers found the same result when treating young mice or cultured BECs from young mice with aged human plasma. This suggested that shared factors in aged mouse and human plasma ramped up VCAM1 expression on BECs. Stop VCAM1, Stop Aging? Anti-VCAM1 antibodies increase the number of proliferating (EdU+) neural progenitor cells (Sox2+) in the subventricular zone (white lines) of the dentate gyri of young mice treated with aged human plasma (left two panels). Anti-VCAM1 antibodies decrease the number of activated (CD68+) microglia (Iba1+) (right two panels). [Courtesy of Yousef et al., BioRxiv, 2018.] So far so good, but does VCAM1 facilitate what aged plasma does to the brain? To find out, the researchers injected an anti-VCAM1 antibody into young animals treated with plasma from old mice or humans. As seen previously, in young brains, aged plasma reduced proliferation of neural progenitor cells, a marker of neurogenesis, and boosted activation of microglia; however, treatment with the VCAM1 antibody completely blocked these effects. The same was true in the context of normal aging, as 16-month-old mice injected with the antibody every three days for three weeks had higher rates of neurogenesis and fewer reactive microglia than untreated mice. Does the VCAM1 need to be on BECs? To find out, the researchers generated mice in which VCAM1 expression can be shut off only in BECs. Doing so between the age of two and 16 months resulted in old mice having more neurogenesis and less neuroinflammation than did mice that had been expressing VCAM1 on BECs all along. The findings suggest that VCAM1 expression on BECs somehow mediates the detrimental effects of aged plasma on the brain, Wyss-Coray told the audience. It is unclear how this works, but Wyss-Coray hypothesized that systemic factors ramp up VCAM1 expression on the brain endothelium, and possibly also VLA-4 expression on circulating leukocytes. This would lead to leukocyte tethering along the luminal side of the BBB, where they might inflame the endothelium and transmit inflammatory mediators into the brain. Either directly or via activation of microglia, these mediators could suppress neurogenesis. The exact sequence of events remains to be discovered. Fielding questions from the audience after his talk, Wyss-Coray added nuance to his findings. He said that using an anti-VLA4 antibody instead of an anti-VCAM1 antibody prevented the age-related increase in microglial activation but not the decline in neurogenesis. When asked whether a VCAM1 antibody might work as an anti-aging therapeutic, Wyss-Coray cautioned that anti-VLA4 antibodies, which are a standard treatment for people with multiple sclerosis and Crohn’s disease, cause cancer in a small proportion of patients. Given the severity of those diseases, the cancer risk is considered acceptable. “VCAM1 antibodies would probably be seen in a similar light: If they are efficacious against AD or a similar neurodegenerative disease, a black label might be accepted, and the potential cancer risk would be carefully monitored,” he told Alzforum later. Jonas Neher of the German Center for Neurodegenerative Diseases in Tübingen was intrigued by the work. Neher recently reported that systemic inflammation steers the course of future microglial responses to neurodegenerative disease in the brain (Apr 2018 news). However, Neher contends that soluble factors, such as cytokines, are highly likely to play a role in signaling into the brain. Wyss-Coray agreed, adding that soluble factors could still influence the brain via leukocytes, by upregulating both VCAM1 on the endothelium and VLA-4 on leukocytes. ‘Fit’ Infusions, Youthful Fractions While the new data on VCAM1 speak to how old blood ages the brain, the Keystone meeting also featured findings about how young blood, perhaps even that of athletes, rejuvenates. Zurine de Miguel, a senior scientist in Wyss-Coray’s lab, reported that not just youth but physical fitness might bestow neurogenesis powers onto blood. De Miguel found that plasma collected from mice with access to a running wheel and infused into sedentary mice boosted the birth of newborn neurons in them. Previous studies have linked exercise to neurogenesis, and De Miguel’s findings now suggest that factors in the plasma facilitate the benefit. De Miguel also reported that so-called “runner’s plasma” boosted expression of neuroplasticity genes in recipients, and dampened their inflammatory response to lipopolysaccharide. De Miguel demurred when asked to opine whether regular infusions with the blood of exercisers could substitute for actually working out. Eva Czirr of Alkahest, a biotech company in San Carlos, California, presented clinical findings based on Wyss-Coray’s research. He co-founded Alkahest with Karoly Nikolich in hopes of parlaying plasma products into treatments for neurodegenerative and other age-related diseases. The company completed a small Phase 1 study testing the safety of “young plasma” derived from 18- to 22-year-old donors in recipients with mild to moderate AD (Dec 2017 conference news).  As that trial was ongoing, Czirr and colleagues zeroed in on a plasma fraction—dubbed GRF6019—that they speculate will contain the beneficial properties of whole plasma without its downsides. Comprising about 400 proteins, GRF6019 is devoid of immunoglobulins and clotting factors; this eliminates the need to match recipients to donors and reduces the risk of stroke. Plasma fractions are made from pooled plasma of many donors, facilitating production of large, standardized batches. Alkahest acquires its plasma fractions from Barcelona-based Grifols, the world’s largest producer of blood products. Czirr said that Grifols collects an average of 25,000 plasma donations per day around the world. At Keystone, Czirr reported that GRF6019 had lasting benefits in old mice. Three months after receiving intravenous infusions, the mice still had elevated rates of neurogenesis, lower markers of neuroinflammation, and performed better on tests of memory than their untreated counterparts. In addition, Czirr reported that Alkahest’s Phase 2 clinical trial is officially underway (clinicaltrials.gov). The trial tests GRF6019 in 40 participants with clinically diagnosed mild to moderate AD. They will be equally randomized to receive a low or high dose of GRF6019 intravenously for five consecutive days on the first week of the trial, then again for five days during week 13. The primary outcome measure is safety; cognitive, functional, and neuropsychological tests make up secondary outcomes. Participants will be monitored for a total of six months during the trial.—Jessica Shugart REFERENCES News Citations Paper Alert: Do Blood-Borne Factors Control Brain Aging? 31 Aug 2011 In Revival of Parabiosis, Young Blood Rejuvenates Aging Microglia, Cognition 5 May 2014 Young Blood a Boon for APP Mice 14 Sep 2016 Stuck in the Past? Microglial Memories Dictate Response to Aβ 19 Apr 2018 Blood, the Secret Sauce? Focus on Plasma Promises AD Treatment 14 Dec 2017 Therapeutics Citations Young Plasma GRF6019 Paper Citations Vanlandewijck M, He L, Mäe MA, Andrae J, Ando K, Del Gaudio F, Nahar K, Lebouvier T, Laviña B, Gouveia L, Sun Y, Raschperger E, Räsänen M, Zarb Y, Mochizuki N, Keller A, Lendahl U, Betsholtz C. A molecular atlas of cell types and zonation in the brain vasculature. Nature. 2018 Feb 14; PubMed. External Citations Yousef et al., 2018 clinicaltrials.gov) FURTHER READING No Available Further Reading

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Research published today in the journal Nature provides new understanding about how drugs can repair damaged brain cells that cause disability in patients with multiple sclerosis. Led by researchers at Case Western Reserve ...

Intermittent fasting confers protection in the multiple sclerosis animal model through
effects on the gut microbiota; similar changes to the gut microbiota were observed
in relapsing multiple sclerosis patients undergoing intermittent energy restriction.

Glioblastomas remain one of the most aggressive and lethal tumours, with no effective treatments available. Here, Xandra Breakefield and colleagues examine the ways in which glioblastomas manipulate brain cells and immune cells in their environment to support tumour growth and the opportunities...

Zika virus infection of pregnant women can cause congenital brain defects. Here, Coffey et al. establish a pregnant rhesus macaque model, using intravenous and intraamniotic route of infection, that reliably reproduces fetal neurologic defects of congenital Zika syndrome in humans.

Alzheimer is the severe version of dementia. Stem cell therapy is an alternative treatment option for Alzheimer Disease. Natural Cure No Side Effects, Call us: +91-9654321400.

Adeno-associated viral (AAV) vectors are a rapidly emerging gene therapy platform for the treatment of neurological diseases. In preclinical studies, transgenes encoding therapeutic proteins, microRNAs, antibodies or gene-editing machinery have been successfully delivered to the central nervous system with natural or engineered viral capsids via various routes of administration. Importantly, initial clinical studies have demonstrated encouraging safety and efficacy in diseases such as Parkinson disease and spinal muscular atrophy, as well as durability of transgene expression. Here, we discuss key considerations and challenges in the future design and development of therapeutic AAV vectors, highlighting the most promising targets and recent clinical advances.

In summary, these data suggest an anti-inflammatory role of DMF and its metabolite MMF on the B cell compartment.

Keywords Multiple sclerosis, dimethyl fumarate, B cells, cytokines, follicular helper T cells
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A blog on multiple sclerosis research...

Bioinformatic analysis using GO analysis for the targets of differentially expressed miRNAs revealed enrichment of cell cycle and developmental processes. Furthermore, WNT, CCKR, PDGF, EGF, p53, and NOTCH signaling pathways were among the top enriched pathways. Thus, our study provides evidence for the involvement of ZV E protein and novel insights into the molecular mechanism through identification of miRNA circuitry.

We found that DMF reduces the frequency of circulating antigen–experienced B cells, a reduction likely related to a reduced frequency of follicular helper T (TFH) cells and an increased frequency of follicular regulatory T (TFR) cells. Studying the impact of monomethyl fumarate (MMF), the primary metabolite of DMF, on B cell effector function in vitro showed that MMF increased the frequency of transforming growth factor (TGF)-β-producing B cells and decreased the frequency of B cells secreting lymphotoxin (LT)-α, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and to a lesser extent IL-10.

Conclusion:
In summary, these data suggest an anti-inflammatory role of DMF and its metabolite MMF on the B cell compartment.

Keywords Multiple sclerosis, dimethyl fumarate, B cells, cytokines, follicular helper T cells

To what extent does the subarachnoid cerebrospinal fluid (CSF) compartment communicate directly with the extravascular compartment of human brain tissue? Interconnection between the subarachnoid CSF compartment and brain perivascular spaces is reported in some animal studies, but with controversy, and in vivo CSF tracer studies in humans are lacking. In the present work, we examined the distribution of a CSF tracer in the human brain by MRI over a prolonged time span. For this, we included a reference cohort, representing close to healthy individuals, and a cohort of patients with dementia and anticipated compromise of CSF circulation (idiopathic normal pressure hydrocephalus). The MRI contrast agent gadobutrol, which is confined to the extravascular brain compartment by the intact blood-brain barrier, was used as a CSF tracer. Standardized T1-weighted MRI scans were performed before and after intrathecal gadobutrol at defined time points, including at 24 hours, 48 hours, and 4 weeks. All MRI scans were aligned and brain regions were segmented using FreeSurfer, and changes in normalized T1 signals over time were quantified as percentage change from baseline. The study provides in vivo evidence of access to all human brain subregions of a substance administered intrathecally. Clearance of the tracer substance was delayed in the dementia cohort. These observations translate previous findings in animal studies into humans and open new prospects concerning intrathecal treatment regimens, extravascular contrast-enhanced MRI, and assessment of brain clearance function.

JUNE 19, 2018 TAGS: JAENISCH LABSTEM CELLS + THERAPEUTIC CLONINGIMMUNE SYSTEMNERVOUS SYSTEM Cambridge, MA  – Scientists turn to model organisms, like mice and yeast, to investigate the biology underlying emerging diseases. But for the Zika virus, the lack of a good model hampered this type of research. Now, a team of researchers in the laboratory of Whitehead Institute Founding Member Rudolf Jaenisch has devised a way to model Zika and other neural diseases in a dish. Their work is described this week in the journal PNAS. The Zika virus was identified in 1947 in Uganda, but a 2013 epidemic in French Guinea first brought it to the public’s attention. As the disease spread throughout the Americas and the Caribbean in 2014, abnormalities, such as microcephaly in newborns, were increasingly reported when mothers were infected during their first trimester. Scientists’ efforts to better understand the virus and its mechanisms quickly hit a snag: mice, which are often used to model disease pathology, are not vulnerable to the Zika virus unless their innate immune defenses are knocked out. Additionally, neural diseases, such as those that cause microcephaly, affect cells that reside deep in the brain, and they cannot be easily accessed for observation and manipulation. In order to circumvent these challenges and to model Zika in the lab, the researchers turned to induced pluripotent stem cells (iPSCs)--adult cells that have been pushed back to a embryonic stem cell-like state. iPSCs can in turn be nudged to mature into almost any cell type in the body. In previous work, Julien Muffat and Yun Li, former postdoctoral researchers in the Jaenisch lab, were the first to use iPSCs to create microglia, the specialized immune cells that maintain the brain and spinal cord and care for them after injury. In the current work, Muffat and Li teamed up with Attya Omer, also a graduate student in the Jaenisch lab, and Lee Gehrke’s lab at MIT to study the effect of the Zika virus on iPSC-derived versions of three neural cell types critical during human fetal brain development: microglia, neural progenitors, and astrocytes. Whether the Zika virus can infect these cells and how well the cells can clear the virus could provide insight into why the virus can cause birth defects like microcephaly. Using their model, the team determined that after being infected with a strain derived from the initial Ugandan Zika virus, microglia can survive and can continue to harbor the virus. This is important because in a developing embryo, microglia move from the yolk sac to the developing brain very early in gestation. The study shows that, like their in vivo counterparts, iPSC-derived microglia could invade the immature neural tissue of a brain organoid, and pre-infected microglia could transfer the virus to the organoids. According to Muffat, this suggests that if microglial precursors are infected before their journey, they could shuttle the Zika virus to the developing brain and infect the neural progenitors residing there. Neural progenitor cells, which during gestation produce the neurons and glia that constitute the majority of the human brain, are particularly vulnerable to the Zika virus and die when infected. To better understand why these cells are so susceptible, the team compared how the Zika virus and the closely related dengue virus affect the neural progenitor cells. Dengue, which does not cause birth defects like microcephaly, triggers a strong cellular immune response, called interferon, in the neural progenitors, which enables the progenitor cells to efficiently fight and clear the dengue virus. In sharp contrast, when exposed to the Zika virus, neural progenitors mount little if any interferon immune defense. Pretreating the neural progenitor cells with interferon before exposure to the Zika virus impedes the virus’s progression and proliferation, and reduces cell death. These results suggest that therapeutically altering interferon levels could prevent some of the more dire effects of Zika infection on the neural progenitor cells. According to the team, using iPSC-derived cells has great potential for modeling Zika virus as well as many other diseases that affect the central nervous system. This work was supported by the European Leukodystrophy Association, the Brain & Behavior Research Foundation, the Simons Foundation (SFARI 204106), the International Rett Syndrome Foundation, Howard Hughes Medical Institute, the National Institutes of Health (NIH grants HD 045022, R37-CA084198, AI100190), the ELA Foundation, the Emerald Foundation, and Biogen. Jaenisch is a cofounder of Fate Therapeutics, Fulcrum Therapeutics, and Omega Therapeutics. Written by Nicole Giese Rura *** Rudolf Jaenisch's primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a professor of biology at Massachusetts Institute of Technology.  *** Full citation: “Human Induced Pluripotent Stem Cell-derived Glial Cells and Neural Progenitors Display Divergent Responses to Zika and Dengue Infections” PNAS, online June 18, 2018. 

Alterations in circulating (c)Tfh distribution and/or function have been associated with autoimmune diseases including MS. Dimethyl fumarate (DMF) is a recently approved first-line treatment for relapsing–remitting MS (RRMS) patients whose mechanism of action is not completely understood. The aim of our study was to compare cTfh subpopulations between RRMS patients and healthy subjects and evaluate the impact of DMF treatment on these subpopulations, relating them to changes in B cells and humoral response. We analyzed, by flow cytometry, the distribution of cTfh1 (CXCR3+CCR6−), cTfh2 (CXCR3−CCR6−), cTfh17 (CXCR3−CCR6+), and the recently described cTfh17.1 (CXCR3+CCR6+) subpopulations of CD4+ Tfh (CD45RA−CXCR5+) cells in a cohort of 29 untreated RRMS compared to healthy subjects. CD4+ non-follicular T helper (Th) cells (CD45RA−CXCR5−) were also studied. We also evaluated the effect of DMF treatment on these subpopulations after 6 and 12 months treatment. Untreated RRMS patients presented higher percentages of cTfh17.1 cells and lower percentages of cTfh2 cells consistent with a pro-inflammatory bias compared to healthy subjects. DMF treatment induced a progressive increase in cTfh2 cells, accompanied by a decrease in cTfh1 and the pathogenic cTfh17.1 cells. A similar decrease of non-follicular Th1 and Th17.1 cells in addition to an increase in the anti-inflammatory Th2 subpopulation were also detected upon DMF treatment, accompanied by an increase in naïve B cells and a decrease in switched memory B cells and serum levels of IgA, IgG2, and IgG3. Interestingly, this effect was not observed in three patients in whom DMF had to be discontinued due to an absence of clinical response. Our results demonstrate a possibly pathogenic cTfh pro-inflammatory profile in RRMS patients, defined by high cTfh17.1 and low cTfh2 subpopulations that is reverted by DMF treatment. Monitoring cTfh subsets during treatment may become a biological marker of DMF effectiveness.

Objective To determine whether autologous infusions of expanded regulatory T lymphoctyes (Tregs) into patients with amyotrophic lateral sclerosis (ALS) are safe and tolerable during early and later stages of disease.