Neurogenesis is known to take place in the adult brain. This work identifies T lymphocytes and microglia as being important to the maintenance of hippocampal neurogenesis and spatial learning abilities in adulthood. Hippocampal neurogenesis induced by an enriched environment was associated with the recruitment of T cells and the activation of microglia. In immune-deficient mice, hippocampal neurogenesis was markedly impaired and could not be enhanced by environmental enrichment, but was restored and boosted by T cells recognizing a specific CNS antigen. CNS-specific T cells were also found to be required for spatial learning and memory and for the expression of brain-derived neurotrophic factor in the dentate gyrus, implying that a common immune-associated mechanism underlies different aspects of hippocampal plasticity and cell renewal in the adult brain.

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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

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