P-076: Estrogen receptor-selective ligands regulate ApoE expression and neurogenesis in 3xTgAD mouse hippocampus

Abstract

The single amino acid substitutions of apolipoprotein E (ApoE) drive late-onset Alzheimer's disease (AD) in opposite directions. ApoE2 and ApoE3 are protectors from AD progression, but ApoE4 is a major risk factor for AD progression. Population-based investigations indicated that the ApoE4 allele is a major risk factor for ∼50% of AD cases in the United States. Recent data indicated that ectopic expression of ApoE4 increased Amyloid β (Aβ) deposition and burden, while expression of ApoE2/3 markedly reduced the AD pathology progression in DPAPP mouse hippocampus by intracerebral administration of lentiviral vectors expressing the three common human ApoE isoforms. The above data strongly support the idea that regulation of the levels of ApoE in human subjects is a powerful AD-prevention stratagem. We recently demonstrated that ApoE expression could be differentially regulated by estrogen receptor selective ligands in rat hippocampal neurons in vitro and in vivo. This study investigated the impact of ER-selective ligands on ApoE expression and neurogenesis in 3xTgAD mouse SGZ. Methods: ApoE expression, neurogenesis and AD progression in LaFerla 3xTgAD and non-Tg mouse were measured by Western blot, IHC and unbiased stereology. 1) ER-selective ligands differentially regulated ApoE expression in mouse and rat hippocampus; 2) 17β-estradiol reduced Aβ burden in 3xTgAD mouse hippocampus; 3) 17β-estradiol and propyl pyrazole triol (PPT, an ERα-selective ligand which increases ApoE expression) reversed the neurogenic deficits, while diarylpropionitrile (DPN, an ERβ ligand which reduces ApoE expression) had no effect on neurogenesis in the SGZ of 3xTgAD mouse. This study suggests, when ERα- and ERβ-selective ligands are applied to ApoE2/3 and ApoE4 allelic carriers, respectively, that the ERα-specific ligand will reduce AD pathology and enhance neurogenesis in ApoE3/AD carriers, while the ERβ-specific ligand will reduce AD pathology and increase neurogenesis in ApoE4/AD carriers.