Bruce Trapp

....

....

..Finally, surrogate markers of axonal pathology, such as N-acetyl aspartate, can be used to monitor axonal dysfunction, axonal loss and treatment efficiency in patients with MS...

..In this issue of Cell Stem Cell, Windrem et al. (2008) describe the first progenitor cell transplantation paradigm that rescues the neurological phenotypes and increases life spans of mice with inherited myelin disease...

....

..Since neuronal pathology was not a feature of either the acute or immune-mediated lesion, synaptic stripping by activated microglia may have neuroprotective consequences...

..The development of neuroprotective therapies that target these mechanisms might constitute effective adjuncts to currently used immune-modifying agents...

..Finally, studies of the time course of axonal loss, and its mechanisms are critical for effective therapeutic intervention...

..The view that MS can also be considered an inflammatory neurodegenerative disease has important clinical implications for therapeutic approaches, monitoring of patients, and future treatment strategies...

..We studied the following ROIs: normal-appearing white matter (NAWM); regions abnormal only on T2-weighted images (T2 only); and regions abnormal on T2- and T1-weighted images with an abnormal magnetization transfer ratio (T2/T1/MTR)...

..This report poses the therapeutic challenge of facilitating TRAIL expression in the periphery while inhibiting TRAIL in the CNS...

..This study identified a major myelin protein in zebrafish, 36K, as a member of the SDR superfamily; an expression pattern similar to other myelin genes was demonstrated...

....

..These data support the hypothesis that CD9 helps form the tetraspanin web beneath the plasma membranes of progenitor cells committed to oligodendrogenesis, but that CD9 is not essential for oligodendrogenesis and myelination...

..We propose that betaT4 cells are an endogenous cell source that can be recruited to promote neural repair in the adult telencephalon...

..These data support the hypothesis that the P0-PLP shift during vertebrate evolution provided a vital neuroprotective function to myelin-forming CNS glia...

..This chronic-relapsing EAE model provides an excellent platform for 2 critical objectives: investigating mechanisms of axon loss and evaluating efficacy of neuroprotective therapies...

..These results support neurogenesis in a subpopulation of demyelinated subcortical white matter lesions in multiple sclerosis brains...

..In addition, the results indicate that neuronal adaptation can increase N-acetylaspartate levels, and that 5 to 20% of the N-acetylaspartate in developing white matter is synthesized by proliferating oligodendrocyte progenitor cells...

..These data support the hypotheses that P(0) protein is required for and can induce S-L incisures and that P(0)-induced CNS incisures can be detrimental to axonal function...

..Understanding the cellular interactions between premyelinating oligodendrocytes, axons, and the microenvironment of lesions of multiple sclerosis may lead to effective strategies for enhancing remyelination...

..Therapeutic interventions directed toward each of these mechanisms need to be tested for their efficacy in enhancing axon survival and, ultimately, their ability to delay progression of neurologic disability in patients with MS...

..Advances in our understanding of NG2 glia in human tissues will require the development of more robust markers for their detection in routinely processed human specimens...

..In response to insufficient ATP production, demyelinated axons increase the size of stationary mitochondrial sites and thereby balance ATP production with the increased energy needs of nerve conduction...

..Further analysis of the effects of chemokine receptor blockade may need to focus on leukocyte activation within the affected CNS as well as trafficking events...

..Beta(IV) tubulin may play a role in establishing the oligodendrocyte MT network, which is essential for the transport of myelin proteins, lipids, and RNA during myelination...

....

..Induction of CNTF signalling and the anti-apoptotic molecule, Bcl2, thus represents a compensatory response to disease pathogenesis and a potential therapeutic target in MS patients...

..Based upon these and previous studies, we postulate that neuronally enriched Bace1 cleaves neuregulin-1 and that processed neuregulin-1 regulates myelination by means of phosphorylation of Akt in myelin-forming cells...

..Pharmacological inhibition of BACE1 should be carefully monitored to avoid alteration of signaling pathway that regulates remyelination...

..These data provide additional evidence that oligodendrogenesis is differentially regulated in white matter and gray matter and implicate PLP/DM20 as a modulator of these differences...

..Endothelial cells were VCAM-1-negative in both lesion and non-lesion MS brain tissue. This report is the first to document direct microglial interaction with oligodendrocytes in MS...

..Elucidation of the endogenous cell survival pathways involved in preconditioning has significant clinical implications for preventing neuronal damage in susceptible patients...

..NG2(+) cells appear prior to the expression of A2B5(+) cells and generate A2B5(+) cells. We propose that during development NG2(+)/A2B5(-) cells (pre-OPCs) represent the direct ancestor to A2B5(+) O2A progenitor cells (OPCs)...

..disease, and Devic's acute neuromyelitis optica or are there distinct nosological entities? As for autoimmunisation which leads to the selective destruction of myelin, is it primary or secondary to an oligodendrocytic apoptotic process?..

..Maintenance of synaptic connections should be considered as a therapeutic target for slowing progression of neurological disability in primary diseases of myelin...

..To date, however, the distribution of Na+/K+ ATPase has not been studied in MS lesions...

..Elucidating the mechanisms that orchestrate neuronal diseases should facilitate development of neuroprotective and neurorestorative strategies...

..05). These results indicate that the cerebral cortex is likely to be a predilection site for MS lesions and identify general cortical subpial demyelination as a distinct pattern occurring in a significant subpopulation of MS patients...

..These data support the concept that 4.1G plays an important role in the membrane expansion and specialization that occurs during formation and maintenance of myelin internodes in the peripheral nervous system...

..The presence of attractive cross-bridging interactions contributes only modestly to structure for moderate degrees of cross-bridging and leads to NF aggregation for extensive cross-bridging...

..Loss of glial support causes progressive axon degeneration and possibly local inflammation, both of which are likely to contribute to a variety of neuronal diseases in the central and peripheral nervous systems...

..Among the models tested, a model in which the filaments interact through a long-range repulsive force is most consistent with the results of our analysis...

..6 and NCX in acute lesions but independent of coexpression of these 2 molecules in chronic lesions...

..Our observations strengthen the notion that PDGF is an important effector molecule in postnatal CNS development...

..Our findings demonstrate that diffraction can provide a quantitative basis for understanding, at a molecular level, the membrane packing defects that occur in internodal myelin in demyelinating peripheral neuropathies...

..HMW hyaluronan may therefore contribute substantially to remyelination failure by preventing the maturation of OPCs that are recruited to demyelinating lesions...

..However, presynaptic endings in both the presence and absence of Wld(s) showed high accumulations of mitochondria and synaptic vesicles, implicating errors of retrograde transport as a consequence of SOD1-mutant damage to axons...

....

..Collectively, our studies should identify new targets for therapeutic intervention that will reduce and delay neurodegeneration and the progression of permanent neurological disability in MS patients. ..

..Collectively, these studies should identify therapeutic targets that enhance remyelination and reduce the progression of neurological disability in MS patients. ..

....

..The results will contribute to understanding myelin disease pathology and provide clues for effective future therapeutic strategies for treating primary myelin diseases. ..

..Collectively, these studies should identify therapeutic targets that enhance remyelination and reduce the progression of neurological disability in MS patients. ..

....

..If it can be demonstrated that these molecules play an essential role in leukocyte trafficking, they become attractive targets for therapeutic intervention in MS. ..

..abstract_text> ..

..We will study MS patients with reduced memory, develop brain imaging techniques to identify MS patients at risk for memory problems and identify ways to treat MS patients with memory loss. ..