Human apolipoprotein E4 modulates the expression of Pin1, Sirtuin 1, and Presenilin 1 in brain regions of targeted replacement apoE mice

Abstract

The apolipoprotein E4 (apoE4) allele is consistently associated with increased risk for Alzheimer's disease (AD). We investigated the molecular mechanism of this susceptibility by analyzing the levels of genes involved in AD pathogenesis in transgenic mice expressing human apoE3 or apoE4 isoforms. mRNA and protein levels of Pin1, Sirtuin 1 (Sirt1), Presenilin 1 (PS1), and pro-Brain-derived Neurotrophic Factor (BDNF) were analyzed in brain regions affected by neuropathological changes in AD. Pin1 mRNA was significantly higher in the hippocampus of apoE4 mice than in apoE3 controls, whereas lower expression was detected in the entorhinal and parietal cortices. Reduced Pin1 levels may increase neurofibrillary degeneration and amyloidogenic processes, while compensatory mechanisms may take place in the hippocampus to balance spatial memory deficits. Sirt1 levels were significantly reduced in the frontal cortex of apoE4 mice. Sirt1 reduction may hinder its protective role against the formation of plaques and tangles and diminish its anti-inflammatory actions. Sirt1 decrease may also play a role in apoE4-associated memory impairments. Moreover, in apoE4 mice PS1 mRNA levels were lower in the frontal cortex. Lower PS1 expression may hamper γ-secretase function, thus affecting amyloid precursor protein processing. Pro-BDNF mRNA levels did not differ between apoE3 and apoE4 mice in any region analyzed. This study showed dysregulated expression of Pin1, Sirt1, and PS1 genes in different cerebral areas of apoE4 mice, suggesting that these changes may play a role in the mechanism of AD vulnerability.

Keywords: AD; APP; Alzheimer’s disease; Aβ; BDNF; Brain-derived Neurotrophic Factor; DDCt; Delta–Delta Ct; EDTA; Forkhead box protein O; FoxO; LDL; NF-κB; NT; Nuclear factor κ B; PS1; Pin1; Presenilin 1; RT-qPCR; S.E.M.; Sirt1; Sirtuin 1; amyloid beta peptide; amyloid precursor protein; apoE; apoE TR mice; apolipoprotein E; apoliporpotein E; ethylenediaminetetraacetic acid; human apoE3- and apoE4-targeted replacement mice; low-density lipoprotein; neurofibrillary tangles; reverse transcription quantitative real-time polymerase chain reaction; standard error of the mean.