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The innate immune system is strongly implicated in the pathogenesis of Alzheimer’s disease (AD). In contrast, the role of adaptive immunity in AD remains largely unknown. However, numerous clinical trials are testing vaccination strategies for AD, suggesting that T and B cells play a pivotal role in this disease. To test the hypothesis that adaptive immunity influences AD pathogenesis, we generated an immune-deficient AD mouse model that lacks T, B, and natural killer (NK) cells. The resulting “Rag-5xfAD” mice exhibit a greater than twofold increase in β-amyloid (Aβ) pathology. Gene expression analysis of the brain implicates altered innate and adaptive immune pathways, including changes in cytokine/chemokine signaling and decreased Ig-mediated processes. Neuroinflammation is also greatly exacerbated in Rag-5xfAD mice as indicated by a shift in microglial phenotype, increased cytokine production, and reduced phagocytic capacity. In contrast, immune-intact 5xfAD mice exhibit elevated levels of nonamyloid reactive IgGs in association with microglia, and treatment of Rag-5xfAD mice or microglial cells with preimmune IgG enhances Aβ clearance. Last, we performed bone marrow transplantation studies in Rag-5xfAD mice, revealing that replacement of these missing adaptive immune populations can dramatically reduce AD pathology. Taken together, these data strongly suggest that adaptive immune cell populations play an important role in restraining AD pathology. In contrast, depletion of B cells and their appropriate activation by T cells leads to a loss of adaptive–innate immunity cross talk and accelerated disease progression.

Background Axl, together with Tyro3 and Mer, constitute the TAM family of receptor tyrosine kinases. In the nervous system, Axl and its ligand Growth-arrest-specific protein 6 (Gas6) are expressed on multiple cell types. Axl functions in dampening the immune response, regulating cytokine secretion, clearing apoptotic cells and debris, and maintaining cell survival. Axl is upregulated in various disease states, such as in the cuprizone toxicity-induced model of demyelination and in multiple sclerosis (MS) lesions, suggesting that it plays a role in disease pathogenesis. To test for this, we studied the susceptibility of Axl-/- mice to experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Methods WT and Axl-/- mice were immunized with myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide emulsified in complete Freund's adjuvant and injected with pertussis toxin on day 0 and day 2. Mice were monitored daily for clinical signs of disease and analyzed for pathology during the acute phase of disease. Immunological responses were monitored by flow cytometry, cytokine analysis and proliferation assays. Results Axl-/- mice had a significantly more severe acute phase of EAE than WT mice. Axl-/- mice had more spinal cord lesions with larger inflammatory cuffs, more demyelination, and more axonal damage than WT mice during EAE. Strikingly, lesions in Axl-/- mice had more intense Oil-Red-O staining indicative of inefficient clearance of myelin debris. Fewer activated microglia/macrophages (Iba1+) were found in and/or surrounding lesions in Axl-/- mice relative to WT mice. In contrast, no significant differences were noted in immune cell responses between naïve and sensitized animals. Conclusions These data show that Axl alleviates EAE disease progression and suggests that in EAE Axl functions in the recruitment of microglia/macrophages and in the clearance of debris following demyelination. In addition, these data provide further support that administration of the Axl ligand Gas6 could be therapeutic for immune-mediated demyelinating diseases.

Neural precursor cells (NPCs) offer a promising approach for treating demyelinating diseases. However, the cellular dynamics that underlie transplanted NPC-mediated remyelination have not been described. Using two-photon imaging of a newly developed ventral spinal cord preparation and a viral model of demyelination, we describe the motility and intercellular interactions of transplanted mouse NPCs expressing green fluorescent protein (GFP) with damaged axons expressing yellow fluorescent protein (YFP). Our findings reveal focal axonal degeneration that occurs in the ventral side of the spinal cord within 1 wk following intracranial instillation with the neurotropic JHM strain of mouse hepatitis virus (JHMV). Axonal damage precedes extensive demyelination and is characterized by swelling along the length of the axon, loss of YFP signal, and transected appearance. NPCs engrafted into spinal cords of JHMV-infected mice exhibited diminished migration velocities and increased proliferation compared with transplanted cells in noninfected mice. NPCs preferentially accumulated within areas of axonal damage, initiated direct contact with axons, and subsequently expressed the myelin proteolipid protein gene, initiating remyelination. These findings indicate that NPCs transplanted into an inflammatory demyelinating microenvironment participate directly in therapeutic outcome through the wrapping of myelin around damaged neurons.

ABSTRACTThe abundant axonal microtubule-associated protein tau regulates microtubule and actin dynamics, thereby contributing to normal neuronal function. We examined whether mice deficient in tau (Tau) or with high levels of human tau differ from wild-type (WT) mice in their susceptibility to neuroaxonal injury in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. After sensitization with MOG35–55, there was no difference in clinical disease course between human tau and WT mice, but Tau mice had more severe clinical disease and significantly more axonal damage in spinal cord white matter than those in WT mice. Axonal damage in gray matter correlated with clinical severity in individual mice. By immunoblot analysis, the early microtubule-associated protein-1b was increased 2-fold in the spinal cords of Tau mice with chronic experimental autoimmune encephalomyelitis versus naive Tau mice. This difference was not detected in comparable WT animals, which suggests that there was compensation for the loss of tau in the deficient mice. In addition, levels of the growth arrest–specific protein 7b, a tau-binding protein that is stabilized when bound to tau, were higher in WT than those in Tauspinal cord samples. These data indicate that loss of tau exacerbates experimental autoimmune encephalomyelitis and suggest that maintaining tau integrity might reduce the axonal damage that occurs in inflammatory neurodegenerative diseases such as multiple sclerosis.

Decreased Hepatic Futile Cycling Compensates for Increased Glucose Disposal in the Pten Heterodeficient Mouse Jun Xu 1 , Lori Gowen 2 , Christian Raphalides 2 , Katrina K. Hoyer 3 , Jason G. Weinger 3 , Mathilde Renard 3 , Joshua J. Troke 3 , Bhavapriya Vaitheesyaran 1 , W.N. Paul Lee 4 , Mohammed F. Saad 5 , Mark W. Sleeman 2 , Michael A. Teitell 3 6 and Irwin J. Kurland 1 7 1 Department of Medicine, State University of New York at Stony Brook, Stony Brook, New York 2 Regeneron Pharmaceuticals, Tarrytown, New York 3 Department of Pathology, University of California Los Angeles, Los Angeles, California 4 Department of Pediatrics, Harbor-University of California Los Angeles Biomedical Institute, Torrance, California 5 Department of Preventive Medicine, State University of New York at Stony Brook, Stony Brook, New York 6 Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 7 Departments of Pharmacological Sciences and Physiology and Biophysics, State University of New York at Stony Brook, Stony Brook, New York Address correspondence and reprint requests to Irwin J. Kurland, SUNY at Stony Brook, HSC T-15 Room 060, Stony Brook, NY 11794-8154. E-mail: irwin.kurland{at}stonybrook.edu Abstract Despite altered regulation of insulin signaling, Pten +/− heterodeficient standard diet–fed mice, ∼4 months old, exhibit normal fasting glucose and insulin levels. We report here a stable isotope flux phenotyping study of this “silent” phenotype, in which tissue-specific insulin effects in whole-body Pten +/− -deficient mice were dissected in vivo. Flux phenotyping showed gain of function in Pten +/− mice, seen as increased peripheral glucose disposal, and compensation by a metabolic feedback mechanism that 1 ) decreases hepatic glucose recycling via suppression of glucokinase expression in the basal state to preserve hepatic glucose production and 2 ) increases hepatic responsiveness in the fasted-to-fed transition. In Pten +/− mice, hepatic gene expression of glucokinase was 10-fold less than wild-type ( Pten +/+ ) mice in the fasted state and reached Pten +/+ values in the fed state. Glucose-6-phosphatase expression was the same for Pten +/− and Pten +/+ mice in the fasted state, and its expression for Pten +/− was 25% of Pten +/+ in the fed state. This study demonstrates how intra- and interorgan flux compensations can preserve glucose homeostasis (despite a specific gene defect that accelerates glucose disposal) and how flux phenotyping can dissect these tissue-specific flux compensations in mice presenting with a “silent” phenotype. AUC, area under the curve G6PDH, glucose-6-phosphate dehydrogenase GC/MS, gas chromatography–mass spectrometry glucose-6-P, glucose-6-phosphate HGP, hepatic glucose production HR-dGTT, hepatic recycling deuterated glucose tolerance test HR-GTT, hepatic recycling glucose tolerance test ipGTT, intraperitoneal glucose tolerance test ITT, insulin tolerance test PI3-K, phosphatidylinositol 3-kinase PPAR, peroxisome proliferator–activated receptor PTEN, phosphatase and tensin homolog deleted on chromosome 10 TCA, trichloroacetic acid Footnotes Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted September 6, 2006. Received January 2, 2006. DIABETES

The TAM family of receptor tyrosine kinases (Tyro3, Axl, and Mer), and their ligand Gas6 have important roles in cell survival, maturation, and phagocytosis. Signaling molecules that can modulate disease-induced central nervous system (CNS) damage and maintain cell survival are highly sought after. In several CNS in vitro models, Axl is associated with survival. Axl-/- mice have altered recovery in the cuprizone toxicity model, and Axl is upregulated in EAE, a mouse model of multiple sclerosis (MS). MS is a debilitating neurological disease involving infiltration of inflammatory cells across the blood brain barrier, resulting in demyelinated lesions, axonal damage, neuronal loss, and oligodendrocyte cell death. Using wildtype (WT) and mutant Axl transfected cells we determined that Axl directly bound Grb2 at p821YVN and the p85 subunit of PI3-kinase at pY779ALM and pY 821VNM. Further, p85 indirectly bound to Axl via Grb2. One minute Gas6-stimulation resulted in recruitment of active PI3-kinase to Axl and Akt phosphorylation. Interactions between Axl, p85 and Grb2 were confirmed in O4+ oligodendrocytes immunopanned from day 10 mouse brain homogenates. Examination of Axl-/- and WT C57B16 mice during the acute phase of MOG-induced EAE showed spinal cords from Axl-/- mice had more immune infiltrates and myelin loss. Also, Axl-/- mice had significantly fewer activated microglia/macrophages adjacent to lesions, and visibly more myelin/cellular debris and axonal damage, all contributing to higher clinical scores. Our studies of human brain sections from MS patients suggest that aberrant Gas6/TAM signaling is associated with lesion progression. Full-length membrane-bound Mer, and soluble forms of Axl and Mer were significantly elevated in homogenates from chronic active and chronic silent (established) MS lesions, relative to normal-appearing white matter controls. In addition, soluble Axl and Mer negatively correlated with Gas6 in established MS lesions. Increased soluble Axl and Mer were associated with increased mature ADAM17, mature ADAM10 and Furin, proteins associated with Axl and Mer solubilization. Soluble Axl and Mer are known to act as decoy receptors that block Gas6 binding to membrane-bound receptors. Thus, EAE and MS tissue studies demonstrated that changes or loss in Gas6/TAM receptor signaling contributed to lesion pathology.