The integral membrane glycoprotein presenilin-1 (PS1), in concert with beta-secretase and beta amyloid precursor protein (betaAPP), orchestrate cleavage of betaAPP into amyloidogenic Abeta peptides. To gain further insight into PS1 function, we undertook a gene expression profiling study that interrogated the expression of 12,000 genes in the forebrain of PS1-hypomorphic mice that exhibit highly attenuated PS1 activity. Using stringent RNA screening, DNA array and Northern assay, we report significant down-regulation in the expression of betaAPP and hypoxia inducible factor-1 alpha (HIF-1alpha), and a marked up-regulation in the expression of glial-specific markers that include S100beta protein, glycerol phosphate dehydrogenase, and glial fibrillary acidic protein. These data suggest potential roles for PS1 in the cellular response to hypoxia and glial-specific gene expression.