Alzheimer's disease (AD) is characterized by plaque formation, neuronal loss, and cognitive decline. The functions of the local and systemic immune response in this disease are still controversial. Using AD double-transgenic (APP͞PS1) mice, we show that a T cell-based vaccination with glatiramer acetate, given according to a specific regimen, resulted in decreased plaque formation and induction of neurogenesis. It also reduced cognitive decline, assessed by performance in a Morris water maze. The vaccination apparently exerted its effect by causing a phenotype switch in brain microglia to dendritic-like (CD11c) cells producing insulin-like growth factor 1. In vitro findings showed that microglia activated by aggregated ␤-amyloid, and characterized as CD11b ؉ ͞CD11c ؊ ͞ MHC class II ؊ ͞TNF-␣ ؉ cells, impeded neurogenesis from adult neural stem͞progenitor cells, whereas CD11b ؉ ͞CD11c ؉ ͞MHC class II ؉ ͞TNF-␣ ؊ microglia, a phenotype induced by IL-4, counteracted the adverse ␤-amyloid-induced effect. These results suggest that dendritic-like microglia, by facilitating the necessary adjustment, might contribute significantly to the brain's resistance to AD and argue against the use of antiinflammatory drugs.␤-amyloid ͉ CD11c ͉ T cell vaccination ͉ immunomodulation ͉ neurodegeneration

Infiltrating T cells and monocyte-derived macrophages support central nervous system repair. Although infiltration of leucocytes to the injured central nervous system has recently been shown to be orchestrated by the brain's choroid plexus, the immunological mechanism that maintains this barrier and regulates its activity as a selective gate is poorly understood. Here, we hypothesized that CD4(+) effector memory T cells, recently shown to reside at the choroid plexus stroma, regulate leucocyte trafficking through this portal through their interactions with the choroid plexus epithelium. We found that the naïve choroid plexus is populated by T helper 1, T helper 2 and regulatory T cells, but not by encephalitogenic T cells. In vitro findings revealed that the expression of immune cell trafficking determinants by the choroid plexus epithelium is specifically induced by interferon-γ. Tumour necrosis factor-α and interferon-γ reciprocally controlled the expression of their receptors by the choroid plexus epithelium, and had a synergistic effect in inducing the epithelial expression of trafficking molecules. In vivo, interferon-γ-dependent signalling controlled trafficking through the choroid plexus; interferon-γ receptor knockout mice exhibited reduced levels of T cells and monocyte entry to the cerebrospinal fluid and impaired recovery following spinal cord injury. Moreover, reduced expression of trafficking molecules by the choroid plexus was correlated with reduced CD4(+) T cells in the choroid plexus and cerebrospinal fluid of interferon-γ receptor knockout mice. Similar effect on the expression of trafficking molecules by the choroid plexus was found in bone-marrow chimeric mice lacking interferon-γ receptor in the central nervous system, or reciprocally, lacking interferon-γ in the circulation. Collectively, our findings attribute a novel immunological plasticity to the choroid plexus epithelium, allowing it to serve, through interferon-γ signalling, as a tightly regulated entry gate into the central nervous system for circulating leucocytes immune surveillance under physiological conditions, and for repair following acute injury.

The role of activated microglia (MG) in demyelinating neurodegenerative diseases such as multiple sclerosis is controversial. Here we show that high, but not low, levels of IFN-g (a cytokine associated with inflammatory autoimmune diseases) conferred on rodent MG a phenotype that impeded oligodendrogenesis from adult neural stem/progenitor cells. IL-4 reversed the impediment, attenuated TNF-a production, and overcame blockage of IGF-I production caused by IFN-g. In rodents with acute or chronic EAE, injection of IL-4-activated MG into the cerebrospinal fluid resulted in increased oligodendrogenesis in the spinal cord and improved clinical symptoms. The newly formed oligodendrocytes were spatially associated with MG expressing MHC class II proteins and IGF-I. These results point to what we believe to be a novel role for MG in oligodendrogenesis from the endogenous stem cell pool. IntroductionRecovery from acute insults or chronic inflammatory and noninflammatory degenerative disorders in the CNS has been attributed to a limited capacity for neurogenesis and oligodendrogenesis, poor regeneration of injured nerves, and extreme vulnerability to degenerative conditions. Studies have demonstrated that the adult CNS contains stem cells that can give rise, albeit to a limited extent, both to neurons (1) and to oligodendrocytes (2) throughout life. Knowledge of the factors allowing such stem cells to exist, proliferate, and differentiate in the adult individual is a prerequisite for understanding and promoting the conditions conducive to CNS repair. This in turn can be expected to lead to the development of interventions aimed at boosting neural cell renewal from the endogenous stem cell pool or from exogenously applied stem cells.Studies have shown that inflammation within the CNS blocks neurogenesis (3, 4) and causes structural damage to myelin (5, 6). Moreover, "paralysis" of microglia (MG) and/or macrophages arrests progression of the transient monophasic disease EAE (7, 8). All of those findings were interpreted as evidence in support of the traditional view that the effect of local immune cells in the CNS is detrimental, and hence that recovery would require blockage, arrest, or elimination of local immune responses. Likewise, the limited regeneration and excessive vulnerability of CNS neurons under inflammatory conditions or after an acute insult were put down to the poor ability of the CNS to tolerate the immune-derived defensive activity that is often associated with local inflammation and cytotoxicity mediated, for example, by 9) or nitric oxide (10). More recent studies have shown, however, that although an uncontrolled local immune response indeed impairs

We have recently shown that the ability of microglia to effectively fight off aggregated beta-amyloid plaque formation and cognitive loss in transgenic mouse models of Alzheimer's disease (Tg-AD), is augmented in response to T-cell-based immunization, using glatiramer acetate (GA). The immunization increases incidence of local CD11c+ dendritic-like cells. It is unclear, however, whether these dendritic cells are derived from resident microglia or from the bone marrow. To determine the origin of this dendritic-cell population, we used chimeric mice whose bone marrow-derived cells express a transgene that allows the cells to be specifically ablated by diphtheria toxin. We show here that T-cell-based immunization of these mice, using GA, induced the recruitment of bone marrow-derived dendritic cells. Depletion of the dendritic cells by systemic injection of diphtheria toxin resulted in significantly increased formation of amyloid plaques. Thus, recruitment of bone marrow-derived dendritic cells evidently plays a role in reducing plaque formation in a mouse model of Alzheimer's disease.

Immunization with an altered myelin‐derived peptide (MOG45D) improves recovery from acute CNS insults, partially via recruitment of monocyte‐derived macrophages that locally display a regulatory activity. Here, we investigated the local alterations in the cellular and molecular immunological milieu associated with attenuation of Alzheimer’s disease‐like pathology following immunotherapy. We found that immunization of amyloid precursor protein/presenilin 1 double‐transgenic mice with MOG45D peptide, loaded on dendritic cells, led to a substantial reduction of parenchymal and perivascular amyloid beta (Aβ)‐plaque burden and soluble Aβ(1–42) peptide levels as well as reduced astrogliosis and levels of a key glial scar protein (chondroitin sulphate proteoglycan). These changes were associated with a shift in the local innate immune response, manifested by increased Iba1+/CD45high macrophages that engulfed Aβ, reduced pro‐inflammatory (tumor necrosis factor‐α) and increased anti‐inflammatory (interleukin‐10) cytokines, as well as a significant increase in growth factors (IGF‐1 and TGFβ) in the brain. Furthermore, the levels of matrix metalloproteinase‐9, an enzyme shown to degrade Aβ and is associated with glial scar formation, were significantly elevated in the brain following immunization. Altogether, these results indicate that boosting systemic immune cells leads to a local immunomodulation manifested by elevated levels of anti‐inflammatory cytokines and metalloproteinases that contribute to ameliorating Alzheimer’s disease pathology.

Amyotrophic lateral sclerosis (ALS) is a devastating fatal motor neuron disease, for which there is currently no cure or effective treatment. In this disease, local neuroinflammation develops along the disease course and contributes to its rapid progression. In several models of CNS pathologies, circulating immune cells were shown to display an indispensable role in the resolution of the neuroinflammatory response. The recruitment of such cells to the CNS involves activation of the choroid plexus (CP) of the brain for leukocyte trafficking, through a mechanism that requires IFN-␥ signaling. Here, we found that in the mutant SOD1 G93A (mSOD1) mouse model of ALS, the CP does not support leukocyte trafficking during disease progression, due to a local reduction in IFN-␥ levels. Therapeutic immunization of mSOD1 mice with a myelin-derived peptide led to CP activation, and was followed by the accumulation of immunoregulatory cells, including IL-10-producing monocyte-derived macrophages and Foxp3 ϩ regulatory T cells, and elevation of the neurotrophic factors IGF-1 and GDNF in the diseased spinal cord parenchyma. The immunization resulted in the attenuation of disease progression and an increased life expectancy of the mSOD1 mice. Collectively, our results demonstrate that recruitment of immunoregulatory cells to the diseased spinal cord in ALS, needed for fighting off the pathology, can be enhanced by transiently boosting peripheral immunity to myelin antigens.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing fatal neurodegenerative disorder characterized by the selective death of motor neurons (MN) in the spinal cord, and is associated with local neuroinflammation. Circulating CD4+ T cells are required for controlling the local detrimental inflammation in neurodegenerative diseases, and for supporting neuronal survival, including that of MN. T-cell deficiency increases neuronal loss, while boosting T cell levels reduces it. Here, we show that in the mutant superoxide dismutase 1 G93A (mSOD1) mouse model of ALS, the levels of natural killer T (NKT) cells increased dramatically, and T-cell distribution was altered both in lymphoid organs and in the spinal cord relative to wild-type mice. The most significant elevation of NKT cells was observed in the liver, concomitant with organ atrophy. Hepatic expression levels of insulin-like growth factor (IGF)-1 decreased, while the expression of IGF binding protein (IGFBP)-1 was augmented by more than 20-fold in mSOD1 mice relative to wild-type animals. Moreover, hepatic lymphocytes of pre-symptomatic mSOD1 mice were found to secrete significantly higher levels of cytokines when stimulated with an NKT ligand, ex-vivo. Immunomodulation of NKT cells using an analogue of α-galactosyl ceramide (α-GalCer), in a specific regimen, diminished the number of these cells in the periphery, and induced recruitment of T cells into the affected spinal cord, leading to a modest but significant prolongation of life span of mSOD1 mice. These results identify NKT cells as potential players in ALS, and the liver as an additional site of major pathology in this disease, thereby emphasizing that ALS is not only a non-cell autonomous, but a non-tissue autonomous disease, as well. Moreover, the results suggest potential new therapeutic targets such as the liver for immunomodulatory intervention for modifying the disease, in addition to MN-based neuroprotection and systemic treatments aimed at reducing oxidative stress.

BackgroundCirculating immune cells including autoreactive T cells and monocytes have been documented as key players in maintaining, protecting and repairing the central nervous system (CNS) in health and disease. Here, we hypothesized that neurodegenerative diseases might be associated, similarly to tumors, with increased levels of circulating peripheral myeloid derived suppressor cells (MDSCs), representing a subset of suppressor cells that often expand under pathological conditions and inhibit possible recruitment of helper T cells needed for fighting off the disease.Methods and FindingsWe tested this working hypothesis in amyotrophic lateral sclerosis (ALS) and its mouse model, which are characterized by a rapid progression once clinical symptoms are evident. Adaptive transfer of alternatively activated myeloid (M2) cells, which homed to the spleen and exhibited immune suppressive activity in G93A mutant superoxide dismutase-1 (mSOD1) mice at a stage before emergence of disease symptoms, resulted in earlier appearance of disease symptoms and shorter life expectancy. The same protocol mitigated the inflammation-induced disease model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), which requires circulating T cells for disease induction. Analysis of whole peripheral blood samples obtained from 28 patients suffering from sporadic ALS (sALS), revealed a two-fold increase in the percentage of circulating MDSCs (LIN−/LowHLA-DR−CD33+) compared to controls.ConclusionsTaken together, these results emphasize the distinct requirements for fighting the inflammatory neurodegenerative disease, multiple sclerosis, and the neurodegenerative disease, ALS, though both share a local inflammatory component. Moreover, the increased levels of circulating MDSCs in ALS patients indicates the operation of systemic mechanisms that might lead to an impairment of T cell reactivity needed to overcome the disease conditions within the CNS. This high level of suppressive immune cells might represent a risk factor and a novel target for therapeutic intervention in ALS at least at the early stage.