9. Axonal Degeneration and the Pathogenesis of Multiple Sclerosis Bruce Trapp Department of Neuroscience,School of Medicine, Case Western Reserve University, Cleveland, Ohio
10. Introduction MS is heterogenous disease Axonal loss is a histopathological correlate to neurological disability Axonal loss thought to be due to loss of trophic factors provided by oligodendrocytes Progessive axon loss occurs from the onset of disease
11. Mechanisms of Axonal Injury Immune cell-mediated injury Myelin-reactive T cells Macrophages CD8+ T cell-mediated cytotoxicity Glutamate excitotoxicity Demyelinated axons require additional AMPA receptors Leads to accumulation of intracellular Na+ and Ca2+ Nitric oxide (NO)-mediated axonal injury NO secreted from inflammatory cells is associated with axonal damage Na+/Ca2+ channel dysfunction Axonal conduction is a continuous energy dependant process Demyelination disrupts this axonal conduction Na+ channels distributed widely to restore conduction This alterated conduction requires even more energy to function Altered electrical neutrality Also leads to changes in Ca2+ homeostasis Ca2+ mediated degenerative responses and cell death
12. Neuroprotective Therapeutic Strategies in MS Na+ channel blockers Phenytoinand carbamazepine Animal studies show beneficial effect in chronic EAE but withdrawal of these drugs worsens disease Other Na+ channel blockers are being tested Ca2+ channel blockers Increases Ca2+ influx leads to activation of multiple enzymatic processes Calpain– Ca2+ dependant protease that degrades myelin and axonal elements Calpain-inhibitor (eg CYLA) ameliorates axonal breakdown in EAE models Glutamate antagonists Memantine (NMDA antagonist) and NBQX (AMPA antagonist) ameliorates disability in EAE models Insulin-like growth factor-1 (IGF-1) Improve remyelination by promoting oligo function IGF-1 promotes Oligo growth and maturation But results in EAE are conflicting due to variability of EAE models Erythropoietin (Epo) Hemapoietic growth factor widely expressed in CNS Epo in EAE models show anti-inflammatory and neuroprotective effects Epo treated EAE animals show decreased axonal loss
13. Differential accumulation and roles of chondritin sulfate proteoglycans and laminins during de- and remyelination Lorraine LauUniversity of Calgary
14. Concept Axons covered by thick myelin sheaths Injury causing demyelination Axons covered by shorter and thinner myelin
18. Accumulation of ECM componentsUnderstanding the complex interplay between inflammatory molecules, ECM components, and proteases is crucial to promoting repair in MS
19. ECM molecules in CNS Laminins Important for allowing cells to spread/extend processes(permissive substrate) Expression following demyelinating injury is unknown Chondroitin Sulfate Proteoglycans (CSPGs) Common protein core + glycosaminoglycan (GAG) chains Inhibitory in axonal regeneration Expression following demyelinating injury is also unknown
20. How does expression of laminin and CSPGs correlate with de- and remyelination?
21. Animal Model % Demyelination 14 21 CSPG and Laminin staining CSPGs increased expression during demyelination but decreased during remyelination Laminins increased expression during demyelination and this expression persists into remyelination phase
22. Where are these ECM molecules coming from? Macrophages/microglia colocalized with CSPGs (Day 7) Laminincolocalized with GFAP+ astrocytes (Day 21)
23. What happens if we block CSPG biological function? Protein Core Xylazide Attachment of GAG chains CSPG exocytosis
24. What happens if we block CSPG biological function? Day 7 The is a loss of CSPG ECM deposition Day 21 Xylazide treated animals have a decreased lesion size
26. Paraclinical Outcome Measures After Acute Optic Neuritis Optic nerve is site of acute localized inflammatory demyelination Common clinical event during MS Structural and functional assessment of optic nerve is useful for quantitative analysis of axonal degeneration in MS
27. ECM molecules in CNS Divided into 3 divisions: Basement Membrane Surround blood vessels Perineural Nets Stabilizes synaptic plasticity Neural-interstitial Matrix Matrix between neurons and glia Hyaluronanupregulated following demyelination
Editor's Notes
Hyaluronan (also called hyaluronic acid or hyaluronate) is an anionic, non-sulfated glycosaminoglycan distributed widely throughout connective,epithelial, and neural tissues. It is unique among glycosaminoglycans in that it is unsulphated, forms in the plasma membrane instead of the Golgiand can be very large with its molecular weight often reaching the millions.[2] One of the chief components of the extracellular matrix, hyaluronan contributes significantly to cell proliferation and migration
Hyaluronan (also called hyaluronic acid or hyaluronate) is an anionic, non-sulfated glycosaminoglycan distributed widely throughout connective,epithelial, and neural tissues. It is unique among glycosaminoglycans in that it is unsulphated, forms in the plasma membrane instead of the Golgiand can be very large with its molecular weight often reaching the millions.[2] One of the chief components of the extracellular matrix, hyaluronan contributes significantly to cell proliferation and migration
