ABSTRACT
Abnormal tau phosphorylation occurs in several neurodegenerative disorders, including Alzheimer's disease (AD) and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). Here, we compare mechanisms of tau phosphorylation in mouse models of FTDP-17 and AD. Mice expressing a mutated form of human tau associated with FTDP-17 (tau(V337M)) showed age-related increases in exogenous tau phosphorylation in the absence of increased activation status of a number of kinases known to phosphorylate tau in vitro. In a "combined" model, expressing both tau(V337M) and the familial amyloid precursor protein AD mutation APP(V717I) in a CT100 fragment, age-dependent tau phosphorylation occurred at the same sites and was significantly augmented compared to "single" tau(V337M) mice. These effects were concomitant with increased activation status of mitogen-activated protein kinase (MAPK) family members (extracellular regulated kinases 1 and 2, p38, and c-Jun NH(2)-terminal kinase) but not glycogen synthase kinase-3alphabeta or cyclin-dependent kinase 5. The increase in MAPK activation was a discrete effect of APP(V717I)-CT100 transgene expression as near identical changes were observed in single APP(V717I)-CT100 mice. Age-dependent deficits in memory were also associated with tau(V337M) and APP(V717I)-CT100 expression. The data reveal distinct routes to abnormal tau phosphorylation in models of AD and FTDP-17 and suggest that in AD, tau irregularities may be linked to processing of APP C-terminal fragments via specific effects on MAPK activation status.
Subject(s)
MAP Kinase Signaling System , tau Proteins/chemistry , Alzheimer Disease/genetics , Amyloid beta-Peptides/metabolism , Animals , Blotting, Western , Brain/metabolism , Cell Membrane/metabolism , Cyclin-Dependent Kinase 5 , Cyclin-Dependent Kinases/metabolism , DNA, Complementary/metabolism , Enzyme-Linked Immunosorbent Assay , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Glycogen Synthase Kinases/metabolism , Humans , Image Processing, Computer-Assisted , Immunohistochemistry , In Situ Hybridization , Membrane Proteins/chemistry , Mice , Mice, Transgenic , Mutation , Phosphorylation , Prosencephalon/metabolism , Protein Structure, Tertiary , Rhombencephalon/metabolism , Signal Transduction , Time Factors , Transgenes , tau Proteins/metabolismABSTRACT
Establishing the cellular identity in vivo of adult multipotent neural progenitors is fundamental to understanding their biology. We used two transgenic strategies to determine the relative contribution of glial fibrillary acidic protein (GFAP)-expressing progenitors to constitutive neurogenesis in the adult forebrain. Transgenically targeted ablation of dividing GFAP-expressing cells in the adult mouse subependymal and subgranular zones stopped the generation of immunohistochemically identified neuroblasts and new neurons in the olfactory bulb and the hippocampal dentate gyrus. Transgenically targeted cell fate mapping showed that essentially all neuroblasts and neurons newly generated in the adult mouse forebrain in vivo, and in adult multipotent neurospheres in vitro, derived from progenitors that expressed GFAP. Constitutively dividing GFAP-expressing progenitors showed predominantly bipolar or unipolar morphologies with significantly fewer processes than non-neurogenic multipolar astrocytes. These findings identify morphologically distinctive GFAP-expressing progenitor cells as the predominant sources of constitutive adult neurogenesis, and provide new methods for manipulating and investigating these cells.
Subject(s)
Gene Expression Regulation/physiology , Glial Fibrillary Acidic Protein/metabolism , Neuroglia/physiology , Neurons/physiology , Prosencephalon/cytology , Stem Cells/physiology , Analysis of Variance , Animals , Bromodeoxyuridine/metabolism , Cell Count/methods , Cell Differentiation/drug effects , Cell Differentiation/physiology , Cell Size , Doublecortin Domain Proteins , Ganciclovir/pharmacology , Gene Expression Regulation/drug effects , Glial Fibrillary Acidic Protein/genetics , Green Fluorescent Proteins/metabolism , Hippocampus/cytology , Hippocampus/drug effects , Hippocampus/metabolism , Immunohistochemistry/methods , Integrases/metabolism , Mice , Mice, Transgenic , Microtubule-Associated Proteins/metabolism , Neural Cell Adhesion Molecule L1/metabolism , Neuropeptides/metabolism , Olfactory Bulb/cytology , Olfactory Bulb/drug effects , Olfactory Bulb/metabolism , Phosphopyruvate Hydratase/metabolism , Prosencephalon/drug effects , Prosencephalon/physiology , Sialic Acids/metabolism , Stem Cells/drug effects , Thymidine Kinase/genetics , Tubulin/metabolism , beta-Galactosidase/metabolismABSTRACT
As a direct consequence of the sophisticated arrangement of its intrinsic neurons, the gastrointestinal tract is unique among peripheral organs, in its ability to mediate its own reflexes. Neurons of the enteric nervous system are intimately associated with enteric glial cells. These supporting cells do not resemble Schwann cells, the glial cell found in all other parts of the peripheral nervous system, but share many similarities with astrocytes of the central nervous system. Ablation of enteric glial cells in adult transgenic mice has demonstrated that these cells are essential to maintain the integrity of the small intestine. Acute loss of enteric glial cells induces massive pathological changes with similarities to necrotizing enterocolitis (NEC) and early Crohn's disease. These human conditions share some mechanistic similarities. Identification of enteric glial cell dysfunction/loss as sufficient to induce necrotic/inflammatory bowel disease may be important to understand the pathogenesis of both NEC and Crohn's disease.
