The human DIMINUTO/DWARF1 homolog seladin-1 confers resistance to Alzheimer's disease-associated neurodegeneration and oxidative stress

In Alzheimer's disease (AD) brains, selected populations of neurons degener ate heavily, whereas others are frequently spared from degeneration. To add ress the cellular basis for this selective vulnerability of neurons in dist inct brain regions, we compared gene expression between the severely affect ed inferior temporal lobes and the mostly unaffected fronto-parietal cortic es by using an mRNA differential display. We identified seladin-1, a novel gene, which was downregulated in large pyramidal neurons in vulnerable regi ons in AD but not control brains. Seladin-1 is a human homolog of the DIMIN UTO/DWARF1 gene described in plants and Caenorhabditis elegans. Its sequenc e shares similarities with flavin-adenin-dinucleotide (FAD)-dependent oxido reductases. In human control brain, seladin-1 was highly expressed in almos t all neurons. In PC12 cell clones that were selected for resistance agains t AD-associated amyloid-beta peptide (A beta)-induced toxicity, both mRNA a nd protein levels of seladin-1 were approximately threefold higher as compa red with the non-resistant wild-type cells. Functional expression of seladi n-1 in human neuroglioma H4 cells resulted in the inhibition of caspase 3 a ctivation after either A beta-mediated toxicity or oxidative stress and pro tected the cells from apoptotic cell death. In apoptotic cells, however, en dogenous seladin-1 was cleaved to a 40 kDa derivative in a caspase-dependen t manner. These results establish that seladin-1 is an important factor for the protection of cells against A beta toxicity and oxidative stress, and they suggest that seladin-1 may be involved in the regulation of cell survi val and death. Decreased expression of seladin-1 in specific neurons may be a cause for selective vulnerability in AD.