Daniel Offen, Ronit Mosberg-Galili and Eldad Melamed

Apoptosis is a normal feature in the development of the nervous system, however, accumulating evidence strongly suggests that apoptosis also contributes to neuronal cell death in a variety of neurodegenerative diseases and aging. Although the hallmark of brain pathology in multiple sclerosis (MS) is the white matter demyelinating plaque, characterized by myelin destruction and oligodendrocyte loss, recent morphological and proton magnetic resonance spectroscopy studies demonstrated neuritic fragmentation, axonal damage, neuronal loss and brain atrophy following demyelination. Analysis of MS lesions showed increases in cell-death-related proteins such as the anti-apoptotic protein Bcl-2, increases in DNA oxidation, and electrophoresed DNA produced a "ladder" characteristic of apoptotic DNA cleavage. Furthermore, it was found that CSF from patients with aggressive MS contained soluble mediators that induce axonal damage and apoptosis of neurons in culture. In experimental autoimmune encephalomyelitis (EAE) model, immunocytochemical identification of glial cells revealed that substantial numbers of cells were dying by apoptotic mechanisms rather than by cell necrosis. Moreover, we have demonstrated that mice overexpressing the anti-apoptotic gene, bcl-2, and mice deficient in the pro-apoptotic gene, bax, show reduced axonal damage and attenuated severity of MOG-induced EAE. These data emphasize the importance of developing neuroprotective therapies and anti-apoptosis strategies in addition to immune specific approaches for treatment of MS.