Reduced Nuclear Factor kappa B activation in dentate gyrus after active avoidance training.

Nuclear Factor kappa B (NF-kappaB) is a transcription factor associated with neuroplasticity and neuronal survival during injury. Although NF-kappaB has been proven to be involved in various processes of repair, there is also evidence that NF-kappaB is associated with learning and memory formation. Our laboratory has previously observed that mice lacking the NF-kappaB p50 subunit are not proficient in learning tasks associated with active avoidance training, an effective learning paradigm. The purpose of this study is to identify changes in NF-kappaB levels after active avoidance training using kappaB-dependent lacZ transgenic mice. Levels of NF-kappaB activity were detected immunohistochemically after active avoidance training in brain regions associated with learning and memory. NF-kappaB activity in trained mice was significantly decreased in the dentate gyrus, but no significant changes were found in other brain regions of trained mice compared to untrained mice. The number of p50-containing neurons was counted in the dentate gyrus and a significant increase was discovered in the trained mice relative to untrained mice. The decrease of NF-kappaB-containing neurons in the dentate gyrus coincides with elevated levels of activated p50 neurons and may be caused by the ability of p50 homodimers to inhibit NF-kappaB transactivation. These results indicate that increased p50 expression down-regulates NF-kappaB activity in the dentate gyrus after exposure to unconditioned stimulus. Therefore, a reduction of NF-kappaB activation and its target genes appears to be a necessary event for early stages of learning and memory consolidation associated with active avoidance training.

Maternal transplantation of human umbilical cord blood cells provides prenatal therapy in Sanfilippo type B mouse model.

Numerous data support passage of maternal cells into the fetus during pregnancy in both human and animal models. However, functional benefits of maternal microchimerism in utero are unknown. The current study attempted to take advantage of this route for prenatal delivery of alpha-N-acetylglucosaminidase (Naglu) enzyme into the enzyme-deficient mouse model of Sanfilippo syndrome type B (MPS III B). Enzymatically sufficient mononuclear cells from human umbilical cord blood (MNC hUCB) were intravenously administered into heterozygote females modeling MPS III B on the 5th day of pregnancy during blastocyst implantation. The major findings were 1) administered MNC hUCB cells transmigrated and diffused into the embryos (E12.5); 2) some transmigrated cells expressed CD34 and CD117 antigens; 3) transmigrated cells were found in both the maternal and embryonic parts of placentas; 4) transmigrated cells corrected Naglu enzyme activity in all embryos; 5) administered MNC hUCB cells were extensively distributed in the organs and the blood of heterozygote mothers at one week after transplantation. Results indicate that prenatal delivery of Naglu enzyme by MNC hUCB cell administration into mothers of enzyme-deficient embryos is possible and may present a significant opportunity for new biotechnologies to treat many inherited disorders.

Lymphopenia and spontaneous autorosette formation in SOD1 mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by motoneuron degeneration. Increasing evidence suggests immune system involvement in ALS pathogenesis but information about peripheral blood characteristics has been lacking. We evaluated hematological and morphological parameters in peripheral blood of G93A SOD1 mice. A significant decrease in white blood cells was found at the end stage of disease. The lymphocyte reduction may suggest immunodeficiency in ALS. Spontaneously forming rosettes with autologous erythrocytes were noted in approximately 28% of lymphocytes in SOD1 mice. To our knowledge, this is the first study characterizing hematology and revealing autorosettes in the SOD1 mouse model of ALS at the terminal phase of disease.

Transplantation of human umbilical cord blood cells benefits an animal model of Sanfilippo syndrome type B.

Sanfilippo syndrome type B is caused by alpha-N-acetylglucosaminidase (Naglu) enzyme deficiency leading to an accumulation of undegraded heparan sulfate, a glycosaminoglycan (GAG). Cell therapy is a promising new treatment and human umbilical cord blood (hUCB) cell transplantation may be preferred for delivery of the missing enzyme. We investigated the ability of mononuclear hUCB cells administered into the lateral cerebral ventricle to ameliorate/prevent histopathological changes in mice modeling Sanfilippo syndrome type B. These are the first results supporting enzyme replacement by administered hUCB cells. In vivo, transplanted hUCB cells survived long-term (7 months), migrated into the parenchyma of the brain and peripheral organs, expressed neural antigens, and exhibited neuron and astrocyte-like morphology. Transplant benefits were also demonstrated by stable cytoarchitecture in the hippocampus and cerebellum, and by reduced GAGs in the livers of treated mutant mice. A hUCB cell transplant may be an effective therapeutic strategy for enzyme delivery in Sanfilippo syndrome type B.