Microglia are the immune cells of the brain. Here we show a massive infiltration of highly ramified and elongated microglia within the core of amyloid plaques in transgenic mouse models of Alzheimer's disease (AD). Many of these cells originate from the bone marrow, and the beta-amyloid-40 and -42 isoforms are able to trigger this chemoattraction. These newly recruited cells also exhibit a specific immune reaction to both exogenous and endogenous beta-amyloid in the brain. Creation of a new AD transgenic mouse that expresses the thymidine kinase protein under the control of the CD11b promoter allowed us to show that blood-derived microglia and not their resident counterparts have the ability to eliminate amyloid deposits by a cell-specific phagocytic mechanism. These bone marrow-derived microglia are thus very efficient in restricting amyloid deposits. Therapeutic strategies aiming to improve their recruitment could potentially lead to a new powerful tool for the elimination of toxic senile plaques.

No abstract

Different patterns of motor nerve activity drive distinctive programs of gene transcription in skeletal muscles, thereby establishing a high degree of metabolic and physiological specialization among myo®ber subtypes. Recently, we proposed that the in¯uence of motor nerve activity on skeletal muscle ®ber type is transduced to the relevant genes by calcineurin, which controls the functional activity of NFAT (nuclear family of activated T cell) proteins. Here we demonstrate that calcineurin-dependent gene regulation in skeletal myocytes is mediated also by MEF2 transcription factors, and is integrated with additional calcium-regulated signaling inputs, speci®cally calmodulin-dependent protein kinase activity. In skeletal muscles of transgenic mice, both NFAT and MEF2 binding sites are necessary for properly regulated function of a slow ®ber-speci®c enhancer, and either forced expression of activated calcineurin or motor nerve stimulation up-regulates a MEF2-dependent reporter gene. These results provide new insights into the molecular mechanisms by which specialized characteristics of skeletal myo®ber subtypes are established and maintained.

Pluripotent stem cells can differentiate into a variety of cell types during tissue development and regeneration. However, it is still unclear whether bone marrow-derived stem cells can migrate across the blood-brain barrier in many regions of the central nervous system (CNS) and if these cells can readily differentiate into functional parenchymal microglia. We thus studied the differentiation fate of bone marrow stem cells upon immigration into the CNS. To this end, we systemically transplanted stem cells that express green fluorescent protein (GFP) into lethally irradiated mice and found that these cells immigrated into the brain parenchyma of many regions of the CNS. Nearly all of the infiltrating cells had a highly ramified morphology and colocalized with the microglial marker iba1. Moreover, these cells expressed high levels of the protein CD11c, indicating that microglia of bone marrow origin may be potent antigen presenting cells. These data suggest that microglia of blood origin could activate cells of the adaptive immune system and cause harm to the CNS. Therefore, these results may have great clinical relevance for both immune-derived neuronal disorders and cancer patients undergoing allogeneic hematopoietic stem-cell transplantation.