Abstract

Previous studies suggest that Alzheimer's disease (AD) neurobiology could not be explained solely by an increase in beta-amyloid levels. Recently, it has been proposed that alterations in brain cholesterol metabolism may contribute to the pathogenesis of AD. In the present work, we focus on early changes in the hippocampal phenotypes of two mouse models in which cognitive impairments were previously described: a) the hypercholesterolemic LDL receptor knockout (LDLr-/-) and b) the APPswe/PS1dE9 (APP/PS1) transgenic model of familial AD. Our initial analysis, subsequent validation and additional experiments at the mRNA and protein levels demonstrate some parallels between the hippocampal phenotypes of these 2 mouse models, however our data suggest that the molecular mechanisms leading to cognitive decline are distinct in LDLr-/- and APP/PS1 animals. Genes related to cytokine signaling were significantly down-regulated in LDLr -/- mice when compared to both the wild-type and APP/PS1 mice, and these include prostaglandin-endoperoxide synthases 1 and 2 (ptgs1 and 2) and nerve grow factor (ngf). We have also detected reduced expression of genes related to lipid metabolism in LDLr -/- mice: peroxisome proliferator activated receptor gamma (pparg), pro-opiomelanocortin-alpha (pomc) and of protein kinase, AMP-activated, alpha 1 catalytic subunit of AMPK (prkaa1). Our array data also indicate that transcriptional activity of early genes involved in memory process, such as FBJ osteosarcoma oncogene (Fos) and the activity regulated cytoskeletal-associated protein (Arc) gene, are increased in the hippocampus of LDLr -/- mice. Several proteins like insulin degrading enzyme (IDE), PGC-1 alpha, OXPHOS 1, NMDAR1 and cyclic AMP response element binding protein (CREB) are up-regulated in the LDLr -/- mice, while in the APP/PS1 mouse model only OXPHOS complexes 2, 3 and 5 are slightly downregulated. Further studies are necessary to understand the molecular pathways involved in memory loss in hypercholesterolemic LDLr -/- mice. (C) 2015 Elsevier Inc. All rights reserved.