Sulfatide, a sphingolipid found in oligodendrocytes and neurons, is significantly and specifically reduced in the CNS of patients with multiple sclerosis (MS) and also of patients with Alzheimer's disease (AD). In both AD and MS the depletion of sulfatide occurs very early in the disease process as sulfatide levels are reduced in AD patients with very mild dementia and in patients with MS prior to demyelination. Although early depletion is consistent with facilitating disease progression, there is currently little evidence that ties sulfatide depletion to pathologic mechanisms associated with either AD or MS. However, using mice that are incapable of synthesizing sulfatide in all cell types and throughout their entire life span, my lab demonstrates (see Preliminary Results) that the absence of sulfatide results (1) in structurally disrupted paranodes, loss of protein membrane domains and myelin instability all of which are seen in MS and (2) in neuronal degeneration, formation of neurofibrillary tangles and compromised synaptic integrity all of which are observed in AD. Based on these findings, I propose that the depletion of sulfatide plays a role in the pathologic consequences observed in both AD and MS. To test this hypothesis we will generate a mouse with loxP sites flanking portions of the gene that encodes cerebroside sulfotransferase (CST), the enzyme that catalyzes the final step of sulfatide synthesis. Exploitation of this """"""""floxed"""""""" mouse will enable us to deplete sulfatide in an age and cell type specific manner. Upon generation of this """"""""floxed"""""""" CST mouse, we will employ a combination of approaches to confirm proper in vivo recombinase excision and the inability to synthesize sulfatide. Generation and analysis of the """"""""floxed"""""""" mouse that is cell type and age specifically depleted in sulfatide is an extremely important step in the advancement of our understanding of the role that sulfatide plays in the pathogenesis of both AD and MS.
Sulfatide is significantly and specifically depleted in Alzheimer's disease and multiple sclerosis;however, the pathologic consequences of this depletion are not known. Here, we will generate a mouse that will provide cell type specific and age specific depletion of this prominent lipid. Generation and analysis of this novel mouse will provide an extremely important step in determining the pathologic consequences of sulfatide depletion and will significantly enhance the advancement of our understanding of the role that sulfatide plays in the pathogenesis of both AD and MS.
| Shroff, S M; Pomicter, A D; Chow, W N et al. (2009) Adult CST-null mice maintain an increased number of oligodendrocytes. J Neurosci Res 87:3403-14 |
