Brain Parenchyma Of Mice Research Articles

Th17 Cells Induce Dopaminergic Neuronal Death via LFA-1/ICAM-1 Interaction in a Mouse Model of Parkinson's Disease.

T helper (Th)17 cells, a subset of CD4+ T lymphocytes, have strong pro-inflammatory property and appear to be essential in the pathogenesis of many inflammatory diseases. However, the involvement of Th17 cells in Parkinson's disease (PD) that is characterized by a progressive degeneration of dopaminergic (DAergic) neurons in the nigrostriatal system is unclear. Here, we aimed to demonstrate that Th17 cells infiltrate into the brain parenchyma and induce neuroinflammation and DAergic neuronal death in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- or 1-methyl-4-phenylpyridinium (MPP+)-induced PD models. Blood-brain barrier (BBB) disruption in the substantia nigra (SN) was assessed by the signal of FITC-labeled albumin that was injected into blood circulation via the ascending aorta. Live cell imaging system was used to observe a direct contact of Th17 cells with neurons by staining these cells using the two adhesion molecules, leukocyte function-associated antigen (LFA)-1 and intercellular adhesion molecule (ICAM)-1, respectively. Th17 cells invaded into the SN where BBB was disrupted in MPTP-induced PD mice. Th17 cells exacerbated DAergic neuronal loss and pro-inflammatory/neurotrophic factor disorders in MPP+-treated ventral mesencephalic (VM) cell cultures. A direct contact of LFA-1-stained Th17 cells with ICAM-1-stained VM neurons was dynamically captured. Either blocking LFA-1 in Th17 cells or blocking ICAM-1 in VM neurons with neutralizing antibodies abolished Th17-induced DAergic neuronal death. These results establish that Th17 cells infiltrate into the brain parenchyma of PD mice through lesioned BBB and exert neurotoxic property by promoting glial activation and importantly by a direct damage to neurons depending on LFA-1/ICAM-1 interaction.

Juvenile striatal white matter is resistant to ischemia-induced damage.

White matter injury following ischemic stroke is a major cause of functional disability. Injury to both myelinated axons and oligodendrocytes, the myelin producing cells in the central nervous system, occurs in experimental models of ischemic stroke. Age-related changes in white matter vulnerability to ischemia have been extensively studied and suggest that both the perinatal and the aged periods are times of increased white matter vulnerability. However, sensitivity of white matter following stroke in the juvenile brain has not been evaluated. Interestingly, the late pediatric period is an important developmental stage, as it is the time of maximal myelination. The current study demonstrates that neurons in late pediatric/juvenile striatum are vulnerable to ischemic damage, with neuronal injury being comparable in juvenile and adult mice following ischemia. By contrast, actively myelinating striatal oligodendrocytes in the juvenile brain are resistant to ischemia, whereas adult oligodendrocytes are quite sensitive. As a result, myelin sheaths are remarkably intact and axons survive well in the injured striatum of juvenile mice. In addition to relative resistance of juvenile white matter, other glial responses were very different in juvenile and adult mice following cerebral ischemia, including differences in astrogliosis, fibrosis, NG2-cell reactivity, and vascular integrity. Together, these responses lead to long-term preservation of brain parenchyma in juvenile mice, compared to severe tissue loss and scarring in adult mice. Overall, the current study suggests that equivalent ischemic insults may result in less functional deficit in children compared to adults and an environment more conducive to long-term recovery. GLIA 2016;64:1972-1986.

A case of mistaken identity: CD11c-eYFP(+) cells in the normal mouse brain parenchyma and neural retina display the phenotype of microglia, not dendritic cells.

Under steady-state conditions the central nervous system (CNS) is traditionally thought to be devoid of antigen presenting cells; however, putative dendritic cells (DCs) expressing enhanced yellow fluorescent protein (eYFP) are present in the retina and brain parenchyma of CD11c-eYFP mice. We previously showed that these mice carry the Crb1(rd8) mutation, which causes retinal dystrophic lesions; therefore we hypothesized that the presence of CD11c-eYFP(+) cells within the CNS may be due to pathology associated with the Crb1(rd8) mutation. We generated CD11c-eYFP Crb1(wt/wt) mice and compared the distribution and immunophenotype of CD11c-eYFP(+) cells in CD11c-eYFP mice with and without the Crb1(rd8) mutation. The number and distribution of CD11c-eYFP(+) cells in the CNS was similar between CD11c-eYFP Crb1(wt/wt) and CD11c-eYFP Crb1(rd8/rd8) mice. CD11c-eYFP(+) cells were distributed throughout the inner retina, and clustered in brain regions that receive input from the external environment or lack a blood-brain barrier. CD11c-eYFP(+) cells within the retina and cerebral cortex of CD11c-eYFP Crb1(wt/wt) mice expressed CD11b, F4/80, CD115 and Iba-1, but not DC or antigen presentation markers, whereas CD11c-eYFP(+) cells within the choroid plexus and pia mater expressed CD11c, I-A/I-E, CD80, CD86, CD103, DEC205, CD8α and CD135. The immunophenotype of CD11c-eYFP(+) cells and microglia within the CNS was similar between CD11c-eYFP Crb1(wt/wt) and CD11c-eYFP Crb1(rd8/rd8) mice; however, CD11c and I-A/I-E expression was significantly increased in CD11c-eYFP Crb1(rd8/rd8) mice. This study demonstrates that the overwhelming majority of CNS CD11c-eYFP(+) cells do not display the phenotype of DCs or their precursors and are most likely a subpopulation of microglia. GLIA 2016. GLIA 2016;64:1331-1349.

T-cell brain infiltration and immature antigen-presenting cells in transgenic models of Alzheimer’s disease-like cerebral amyloidosis

Cerebral beta-amyloidosis, one of the pathological hallmarks of Alzheimer’s disease (AD), elicits a well-characterised, microglia-mediated local innate immune response. In contrast, it is not clear whether cells of the adaptive immune system, in particular T-cells, react to cerebral amyloidosis in AD. Even though parenchymal T-cells have been described in post-mortem brains of AD patients, it is not known whether infiltrating T-cells are specifically recruited to the extracellular deposits of beta-amyloid, and whether they are locally activated into proliferating, effector cells upon interaction with antigen-presenting cells (APCs). To address these issues we have analysed by confocal microscopy and flow-cytometry the localisation and activation status of both T-cells and APCs in transgenic (tg) mice models of AD-like cerebral amyloidosis. Increased numbers of infiltrating T-cells were found in amyloid-burdened brain regions of tg mice, with concomitant up-regulation of endothelial adhesion molecules ICAM-1 and VCAM-1, compared to non-tg littermates. The infiltrating T-cells in tg brains did not co-localise with amyloid plaques, produced less interferon-gamma than those in controls and did not proliferate locally. Bona-fide dendritic cells were virtually absent from the brain parenchyma of both non-tg and tg mice, and APCs from tg brains showed an immature phenotype, with accumulation of MHC-II in intracellular compartments. These results indicate that cerebral amyloidosis promotes T-cell infiltration but interferes with local antigen presentation and T-cell activation. The inability of the brain immune surveillance to orchestrate a protective immune response to amyloid-beta peptide might contribute to the accumulation of amyloid in the progression of the disease.

GABA transmission via ATP-dependent K+channels regulates α-synuclein secretion in mouse striatum

α-Synuclein is readily released in human and mouse brain parenchyma, even though the normal function of the secreted protein has not been yet elucidated. Under pathological conditions, such as in Parkinson's disease, pathologically relevant species of α-synuclein have been shown to propagate between neurons in a prion-like manner, although the mechanism by which α-synuclein transfer induces degeneration remains to be identified. Due to this evidence extracellular α-synuclein is now considered a critical target to hinder disease progression in Parkinson's disease. Given the importance of extracellular α-synuclein levels, we have now investigated the molecular pathway of α-synuclein secretion in mouse brain. To this end, we have identified a novel synaptic network that regulates α-synuclein release in mouse striatum. In this brain area, the majority of α-synuclein is localized in corticostriatal glutamatergic terminals. Absence of α-synuclein from the lumen of brain-isolated synaptic vesicles suggested that they are unlikely to mediate its release. To dissect the mechanism of α-synuclein release, we have used reverse microdialysis to locally administer reagents that locally target specific cellular pathways. Using this approach, we show that α-synuclein secretion in vivo is a calcium-regulated process that depends on the activation of sulfonylurea receptor 1-sensitive ATP-regulated potassium channels. Sulfonylurea receptor 1 is distributed in the cytoplasm of GABAergic neurons from where the ATP-dependent channel regulates GABA release. Using a combination of specific agonists and antagonists, we were able to show that, in the striatum, modulation of GABA release through the sulfonylurea receptor 1-regulated ATP-dependent potassium channels located on GABAergic neurons controls α-synuclein release from the glutamatergic terminals through activation of the presynaptic GABAB receptors. Considering that sulfonylurea receptors can be selectively targeted, our study highlights the potential use of the key molecules in the α-synuclein secretory pathway to aid the discovery of novel therapeutic interventions for Parkinson's disease.

New therapeutic management of Alzheimer’s disease: interest to a phospholipase A2-targeted peptide able to cross the blood-brain barrier through the LDL receptor

New therapeutic management of Alzheimer’s disease: interest to a phospholipase A2-targeted peptide able to cross the blood-brain barrier through the LDL receptor

Infiltration Pattern of Blood Monocytes into the Central Nervous System during Experimental Herpes Simplex Virus Encephalitis.

The kinetics and distribution of infiltrating blood monocytes into the central nervous system and their involvement in the cerebral immune response together with resident macrophages, namely microglia, were evaluated in experimental herpes simplex virus 1 (HSV-1) encephalitis (HSE). To distinguish microglia from blood monocyte-derived macrophages, chimeras were generated by conditioning C57BL/6 recipient mice with chemotherapy regimen followed by transplantation of bone morrow-derived cells that expressed the green fluorescent protein. Mice were infected intranasally with a sub-lethal dose of HSV-1 (1.2x106 plaque forming units). Brains were harvested prior to and on days 4, 6, 8 and 10 post-infection for flow cytometry and immunohistochemistry analysis. The amounts of neutrophils (P<0.05) and «Ly6Chi» inflammatory monocytes (P<0.001) significantly increased in the CNS compared to non-infected controls on day 6 post-infection, which corresponded to more severe clinical signs of HSE. Levels decreased on day 8 for both leukocytes subpopulations (P<0.05 for inflammatory monocytes compared to non-infected controls) to reach baseline levels on day 10 following infection. The percentage of «Ly6Clow» patrolling monocytes significantly increased (P<0.01) at a later time point (day 8), which correlated with the resolution phase of HSE. Histological analysis demonstrated that blood leukocytes colonized mostly the olfactory bulb and the brainstem, which corresponded to regions where HSV-1 particles were detected. Furthermore, infiltrating cells from the monocytic lineage could differentiate into activated local tissue macrophages that express the microglia marker, ionized calcium-binding adaptor molecule 1. The lack of albumin detection in the brain parenchyma of infected mice showed that the infiltration of blood leukocytes was not necessarily related to a breakdown of the blood-brain barrier but could be the result of a functional recruitment. Thus, our findings suggest that blood monocyte-derived macrophages infiltrate the central nervous system and may contribute, with resident microglia, to the innate immune response seen during experimental HSE.

Inside Cover: MiniAp‐4: A Venom‐Inspired Peptidomimetic for Brain Delivery (Angew. Chem. Int. Ed. 2/2016)

Drug delivery to the brain can be enhanced by using peptides that cross the blood–brain barrier. However, the efficacy of peptides is often limited by their protease lability. In their Communication on page 572 ff., M. Teixidó, E. Giralt et al. develop a cyclic peptidomimetic (the key) derived from bee venom that efficiently transports cargoes into the brain parenchyma of mice and across human endothelial cells. This carrier is protease-resistant and has negligible toxicity and immunogenicity.

MiniAp-4: A Venom-Inspired Peptidomimetic for Brain Delivery.

Drug delivery across the blood–brain barrier (BBB) is a formidable challenge for therapies targeting the central nervous system. Although BBB shuttle peptides enhance transport into the brain non‐invasively, their application is partly limited by lability to proteases. The present study proposes the use of cyclic peptides derived from venoms as an affordable way to circumvent this drawback. Apamin, a neurotoxin from bee venom, was minimized by reducing its complexity, toxicity, and immunogenicity, while preserving brain targeting, active transport, and protease resistance. Among the analogues designed, the monocyclic lactam‐bridged peptidomimetic MiniAp‐4 was the most permeable. This molecule is capable of translocating proteins and nanoparticles in a human‐cell‐based BBB model. Furthermore, MiniAp‐4 can efficiently deliver a cargo across the BBB into the brain parenchyma of mice.

MiniAp‐4: A Venom‐Inspired Peptidomimetic for Brain Delivery

AbstractDrug delivery across the blood–brain barrier (BBB) is a formidable challenge for therapies targeting the central nervous system. Although BBB shuttle peptides enhance transport into the brain non‐invasively, their application is partly limited by lability to proteases. The present study proposes the use of cyclic peptides derived from venoms as an affordable way to circumvent this drawback. Apamin, a neurotoxin from bee venom, was minimized by reducing its complexity, toxicity, and immunogenicity, while preserving brain targeting, active transport, and protease resistance. Among the analogues designed, the monocyclic lactam‐bridged peptidomimetic MiniAp‐4 was the most permeable. This molecule is capable of translocating proteins and nanoparticles in a human‐cell‐based BBB model. Furthermore, MiniAp‐4 can efficiently deliver a cargo across the BBB into the brain parenchyma of mice.

Increased brain uptake of targeted nanoparticles by adding an acid-cleavable linkage between transferrin and the nanoparticle core

Most therapeutic agents are excluded from entering the central nervous system by the blood-brain barrier (BBB). Receptor mediated transcytosis (RMT) is a common mechanism used by proteins, including transferrin (Tf), to traverse the BBB. Here, we prepared Tf-containing, 80-nm gold nanoparticles with an acid-cleavable linkage between the Tf and the nanoparticle core to facilitate nanoparticle RMT across the BBB. These nanoparticles are designed to bind to Tf receptors (TfRs) with high avidity on the blood side of the BBB, but separate from their multidentate Tf-TfR interactions upon acidification during the transcytosis process to allow release of the nanoparticle into the brain. These targeted nanoparticles show increased ability to cross an in vitro model of the BBB and, most important, enter the brain parenchyma of mice in greater amounts in vivo after systemic administration compared with similar high-avidity nanoparticles containing noncleavable Tf. In addition, we investigated this design with nanoparticles containing high-affinity antibodies (Abs) to TfR. With the Abs, the addition of the acid-cleavable linkage provided no improvement to in vivo brain uptake for Ab-containing nanoparticles, and overall brain uptake was decreased for all Ab-containing nanoparticles compared with Tf-containing ones. These results are consistent with recent reports of high-affinity anti-TfR Abs trafficking to the lysosome within BBB endothelium. In contrast, high-avidity, Tf-containing nanoparticles with the acid-cleavable linkage avoid major endothelium retention by shedding surface Tf during their transcytosis.

α7 Nicotinic acetylcholine receptor-specific antibody induces inflammation and amyloid β42 accumulation in the mouse brain to impair memory.

Nicotinic acetylcholine receptors (nAChRs) expressed in the brain are involved in regulating cognitive functions, as well as inflammatory reactions. Their density is decreased upon Alzheimer disease accompanied by accumulation of β-amyloid (Aβ42), memory deficit and neuroinflammation. Previously we found that α7 nAChR-specific antibody induced pro-inflammatory interleukin-6 production in U373 glioblastoma cells and that such antibodies were present in the blood of humans. We raised a hypothesis that α7 nAChR-specific antibody can cause neuroinflammation when penetrating the brain. To test this, C57Bl/6 mice were either immunized with extracellular domain of α7 nAChR subunit α7(1-208) or injected with bacterial lipopolysaccharide (LPS) for 5 months. We studied their behavior and the presence of α3, α4, α7, β2 and β4 nAChR subunits, Aβ40 and Aβ42 and activated astrocytes in the brain by sandwich ELISA and confocal microscopy. It was found that either LPS injections or immunizations with α7(1-208) resulted in region-specific decrease of α7 and α4β2 and increase of α3β4 nAChRs, accumulation of Aβ42 and activated astrocytes in the brain of mice and worsening of their episodic memory. Intravenously transferred α7 nAChR-specific-antibodies penetrated the brain parenchyma of mice pre-injected with LPS. Our data demonstrate that (1) neuroinflammation is sufficient to provoke the decrease of α7 and α4β2 nAChRs, Aβ42 accumulation and memory impairment in mice and (2) α7(1-208) nAChR-specific antibodies can cause inflammation within the brain resulting in the symptoms typical for Alzheimer disease.

Phosphodiesterase type 5 inhibitor Tadalafil increases Rituximab treatment efficacy in a mouse brain lymphoma model.

The treatment efficacy of Rituximab on lymphoma as an immunotherapeutic approach is confirmed, but this treatment has limited penetration through the brain micro vessels. Such limitation significantly attenuates the efficacy of systemic administration of this antibody on brain lymphomas. We aimed to confirm that Tadalafil, a long-acting phosphodiesterase type 5 inhibitor, could increase microvascular permeability and Rituximab treatment efficacy in brain lymphomas. We established a mouse brain lymphoma model by planting human-derived lymphoma cell line Raji into brain parenchyma of mice using stereotaxic techniques. After 16 days, 7.0 T magnetic resonance imaging was performed to confirm the presence of the mass. The mice were observed under near-infrared fluorescence after intravenous injection of fluorescence-labeled Rituximab. Evans Blue was used as probe to detect the microvascular permeability of brain lymphomas after Tadalafil administration. Starting from 4 days after implantation, the mice were administered different treatments. Survival analysis of brain lymphoma-loaded mice was performed. Evans Blue detection showed that Tadalafil administration could increase brain vascular permeability in the tumor-bearing group compared with control mice. Rituximab treatment prolonged the survival time of mice compared with the untreated control group (mean 25.75 vs. 20.8 days, p < 0.05). Tadalafil with Rituximab treatment resulted in the longest survival time (29 days, p < 0.05). Rituximab may be a promising therapeutic agent for the treatment of brain lymphoma. Tadalafil can enhance Rituximab treatment efficacy by improving the microvascular permeability in mice brain lymphoma.

The orthotopic xenotransplant of human glioblastoma successfully recapitulates glioblastoma-microenvironment interactions in a non-immunosuppressed mouse model.

BackgroundGlioblastoma (GBM) is the most common primary brain tumor and the most aggressive glial tumor. This tumor is highly heterogeneous, angiogenic, and insensitive to radio- and chemotherapy. Here we have investigated the progression of GBM produced by the injection of human GBM cells into the brain parenchyma of immunocompetent mice.MethodsXenotransplanted animals were submitted to magnetic resonance imaging (MRI) and histopathological analyses.ResultsOur data show that two weeks after injection, the produced tumor presents histopathological characteristics recommended by World Health Organization for the diagnosis of GBM in humans. The tumor was able to produce reactive gliosis in the adjacent parenchyma, angiogenesis, an intense recruitment of macrophage and microglial cells, and presence of necrosis regions. Besides, MRI showed that tumor mass had enhanced contrast, suggesting a blood–brain barrier disruption.ConclusionsThis study demonstrated that the xenografted tumor in mouse brain parenchyma develops in a very similar manner to those found in patients affected by GBM and can be used to better understand the biology of GBM as well as testing potential therapies.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-923) contains supplementary material, which is available to authorized users.

A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse.

Neurogenesis is restricted in the adult mammalian brain; most neurons are neither exchanged during normal life nor replaced in pathological situations. We report that stroke elicits a latent neurogenic program in striatal astrocytes in mice. Notch1 signaling is reduced in astrocytes after stroke, and attenuated Notch1 signaling is necessary for neurogenesis by striatal astrocytes. Blocking Notch signaling triggers astrocytes in the striatum and the medial cortex to enter a neurogenic program, even in the absence of stroke, resulting in 850 ± 210 (mean ± SEM) new neurons in a mouse striatum. Thus, under Notch signaling regulation, astrocytes in the adult mouse brain parenchyma carry a latent neurogenic program that may potentially be useful for neuronal replacement strategies.

Abstract 1484: CD57 defines a novel maker of glioblastoma stem cells that have greater invasive potential than CD133+ tumor cells

Abstract Glioblastoma multiforme (GBM) is the most aggressive and lethal brain tumor that occurs both in children and adults. Diffuse invasion into normal brain tissue is one of the important biologic features that make GBM refractory to conventional therapies. While existing studies on GBM invasion are primarily conducted using tumor core tissues from surgical resections, it is unclear whether unresectable, infiltrative GBM cells would be more informative for studying their invasive nature compared to those in the resected tumor cores. More importantly, little is known if and which cancer stem cell populations are driving glioma invasion. To address these fundamental issues, we utilized our panel of 7 (6 pediatric and 1 adult) patient tumor-derived orthotopic xenograft mouse models of GBM to isolate invasive GBM cells (infiltrating normal mouse brain parenchyma) and tumor core GBM cells and directly compared their biological differences. Our result showed that the invasive cells have stronger neurosphere forming efficiency in vitro in a serial dilution assay and increased tumorigenic capacity after in vivo transplantation (particularly at 100 cells/mouse) compared to the tumor core cells. A screening of putative cancer stem cell markers (CD133, CD15, CD24/CD44, CD57 and CD117) showed that invasive GBM cells are enriched (&amp;gt;2 folds) with CD57+ cells compared to the tumor core cells, and these infiltrating cells were predominantly CD57+/CD133-. Even the CD133+ cells were frequently dual-positive with CD57 (CD33+CD57+), not only in the xenograft tumors but also in a separate set of patient GBM samples. Mechanistically, we found that CD57+ cells expressed high levels of self-renewal genes and tend to stay in G0/G1 phases. In conclusion, we showed that invasive GBM cells are biologically deferent from the matched tumor core cells and identified CD57 as a novel stem cell marker that is associated with GBM infiltration. Our findings suggest that new anti-invasion therapies should target CD57+ cells in addition to CD133+ cells in GBM. Citation Format: Lin Qi, Yu-lun Huang, Mari Kogiso, Hua Mao, Patricia Baxter, Jack MF Su, Laszlo Perlaky, Ching C. Lau, Murali Chintagumpala, Xiao-Nan Li. CD57 defines a novel maker of glioblastoma stem cells that have greater invasive potential than CD133+ tumor cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1484. doi:10.1158/1538-7445.AM2014-1484

Stage-specific requirement for cyclin D1 in glial progenitor cells of the cerebral cortex

Despite the vast abundance of glial progenitor cells in the mouse brain parenchyma, little is known about the molecular mechanisms driving their proliferation in the adult. Here we unravel a critical role of the G1 cell cycle regulator cyclin D1 in controlling cell division of glial cells in the cortical grey matter. We detect cyclin D1 expression in Olig2-immunopositive (Olig2+) oligodendrocyte progenitor cells, as well as in Iba1+ microglia and S100β+ astrocytes in cortices of 3-month-old mice. Analysis of cyclin D1-deficient mice reveals a cell and stage-specific molecular control of cell cycle progression in the various glial lineages. While proliferation of fast dividing Olig2+ cells at early postnatal stages becomes gradually dependent on cyclin D1, this particular G1 regulator is strictly required for the slow divisions of Olig2+/NG2+ oligodendrocyte progenitors in the adult cerebral cortex. Further, we find that the population of mature oligodendrocytes is markedly reduced in the absence of cyclin D1, leading to a significant decrease in the number of myelinated axons in both the prefrontal cortex and the corpus callosum of 8-month-old mutant mice. In contrast, the pool of Iba1+ cells is diminished already at postnatal day 3 in the absence of cyclin D1, while the number of S100β+ astrocytes remains unchanged in the mutant.

“Seeing” and Treating Traumatic Brain Injury in Mice

The biology that underlies long-term sequelae of traumatic brain injury is poorly understood; consequently, treatments are only partially successful. A team from the NIH developed a technique by which they could visualize the meninges and brain parenchyma of living mice through a microscope. They report that acute brain injury first causes production …

Th1 Polarization of T Cells Injected into the Cerebrospinal Fluid Induces Brain Immunosurveillance

Although CD4 T cells reside within the cerebrospinal fluid, it is yet unclear whether and how they enter the brain parenchyma and migrate to target specific Ags. We examined the ability of Th1, Th2, and Th17 CD4 T cells injected intracerebroventricularly to migrate from the lateral ventricles into the brain parenchyma in mice. We show that primarily Th1 cells cross the ependymal layer of the ventricle and migrate within the brain parenchyma by stimulating an IFN-γ-dependent dialogue with neural cells, which maintains the effector function of the T cells. When injected into a mouse model of Alzheimer's disease, amyloid-β (Aβ)-specific Th1 cells target Aβ plaques, increase Aβ uptake, and promote neurogenesis with no evidence of pathogenic autoimmunity or neuronal loss. Overall, we provide a mechanistic insight to the migration of cerebrospinal fluid CD4 T cells into the brain parenchyma and highlight implications on brain immunity and repair.

The protective effect of berberine against neuronal damage by inhibiting matrix metalloproteinase-9 and laminin degradation in experimental autoimmune encephalomyelitis

Objective: This study aims to assess the protective effect of berberine against neuronal damage in the brain parenchyma of mice with experimental autoimmune encephalomyelitis (EAE).Methods: EAE was induced in female C57 BL/6 mice with myelin oligodendrocyte glycoprotein 35–55 amino acid peptide. The berberine treatment was initiated on the day of disease onset and administered daily until the mice were sacrificed. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay, gelatin gel, and gelatin in situ zymography were analysed in this study.Results: Berberine reduced the TUNEL-positive neuronal cells of EAE mice. Gelatin gel and gelatin in situ zymography showed up-regulation of gelatinase activity, which was mainly located in neurons and colocalized with remarkable laminin degradation in EAE mice. Berberine significantly inhibited gelatinase activity and reduced the laminin degradation in EAE mice.Discussion: Our data suggest that berberine could provide protection against neuronal damage in EAE by inhibiting gelatinase activity and reducing laminin degradation. These findings provide further support that berberine can be a potential therapeutic agent for multiple sclerosis.