ENU mutagenesis screening to identify novel regulators of tau-associated toxicity

Abstract

Background: Apolipoprotein E (APOE), a cholesterol carrier associated with atherosclerosis, is a major risk factor for Alzheimer’s disease (AD). The low-density lipoprotein receptor (LDLR) regulates APOE levels in the periphery and in the central nervous system. LDLR is one of the major APOE receptors in the brain and is expressed principally on astrocytes. A number of studies showed that it is involved in amyloid deposition in AD transgenic mice however the findings of previous studies have been controversial.Methods:To investigate the role of LDLR in amyloid deposition we used an APP/PS1 transgenic mouse that develops amyloid plaques with astrocytosis and microgliosis (5xFAD). To elucidate the role of LDLR in relation with APOE we generated 5xFAD transgenic mice on the LDLR or APOE deficient or the APOE/LDLR double deficient background. We have used immunohistochemistry and western blot analysis to analyse the phenotype of the animals. Results: We found that 5xFAD transgenic mice on the LDLR-/-background had increased amyloid plaque deposition compared to 5xFAD control mice. This increase in amyloid plaques was correlated with a significant decrease in astrocytosis and microgliosis in the 5xFAD; LDLR-/-mice. In addition, we found that APOE deletion decreased amyloid plaque formation as expected, but had no effect on astrocytosis or microgliosis in the hippocampus. By comparison 5xFAD; APOE-/-; LDLR-/-double deficient mice had increased amyloid deposition and decreased astrocytosis and microgliosis. Conclusions: The present study shows that LDL deficiency regulates astrocytosis and microgliosis and this effect is independent of APOE, as both 5xFAD; LDLR-/-and 5xFAD; APOE-/-; LDLR-/-mice show reduction in inflammatory response and increase in amyloid deposition compared to control mice. These results demonstrate that LDLR regulates; glial response in this mouse model independently of APOE and aggravates amyloid deposition.