Although some brain regions seem to be more sensitive to cuprizone than others, the widespread CNS demyelination involving corpus callosum, hippocampus, cerebellum, basal ganglia and other white matter rich brain structures have been documented. In addition to reduced myelin content of the forebrain and cerebellum, we demonstrate for the first time pronounced myelin depletion of the ON in mice fed cuprizone. Indeed, electron microscopic analysis highlights reduction in the myelin thickness and compactness, along with shrinkage of the large diameter axons associated with the emergence of loose myelin stacks and subaxolemmal vacuolar elements. A complete lack of myelin breakdown or axonal spheroid blebs in our experimental samples accord with an absence of degeneration of axons and neurons reported for this model. Similar signs of axonopathy with reduction in the axonal caliber followed by degeneration at the later stages have been reported for transgenic mice lacking myelin proteins such as 29,39cyclic LOUREIRIN-B nucleotide 39-phosphodiesterase, proteolipid protein and myelin-associated glycoprotein as well as in autopsies from MS brain. These changes in axonal ultra-structure have been attributed to the fact that oligodendrocytes and myelin integrity, in addition to providing insulation, supply trophic support to axons which is essential for stability and normal functionality. Interestingly, the decrease in the myelin thickness of axons in our model was associated with moderate reduction of their diameter, perhaps a compensatory process, which retained the ��g-ratio’fairly normal. In fact, smaller axon diameter would reduce the capacitative load, Hexamethonium Bromide favouring more effective propagation of action potentials through demyelinated segments; also, it would assist in maintaining ion homeostasis, delaying the onset of irreversible degeneration and neurological decline. It should be emphasized that even though the extent to which cuprizone demyelination reflects MS pathology in humans remains disputable, extensive breakdown of myelin with its depletion in ON documented herein suggest this model as being useful and appropriate for exploring certain aspects of MS patho-biology. Protein misfolding disorders refer broadly to a class of human diseases associated with the failure of a protein or peptide to adopt its native, functional conformation. Such misfolding can lead to the formation of fibrillar aggregates called amyloid. Amyloid fibers typically form as a �� sheet-rich structure in a self-replicating process. These highly ordered arrangements of �� sheets are formed from non-covalent interactions of neighboring polypeptides in which the �� strands run perpendicular to the fibril axis. This fundamental architecture is shared among a variety of proteins associated with unrelated protein conformational disorders, including Alzheimer’s disease and Type II diabetes. Interestingly, significant conformational variation can exist while still maintaining this generic amyloid structure. Such amyloid polymorphism has been most studied in the context of prion strains, but recent data suggest that it is a common feature of many amyloidogenic proteins. Prion diseases, also called transmissible spongiform encephalopathies, represent a subset of protein misfolding disorders that are invariably fatal. These diseases include bovine spongiform encephalopathy in cattle and Creutzfeldt-Jakob disease in humans. TSEs develop when the host-encoded prion protein, PrPC, assumes the abnormal �� sheet-rich PrPSc conformation. This infectious structure self-propagates by sequestering native PrPC and templating further conversion to PrPSc. Initial transmission experiments with PrPSc encountered what is now known.