APOE4 is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). ApoE4 increases brain amyloid-β (Aβ) pathology relative to other ApoE isoforms1. However, whether APOE independently influences tau pathology, the other major proteinopathy of AD and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knockin (KI) or ApoE knockout (KO) background, we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by 3 months of age compared to P301S/E2, P301S/E3 and P301S/EKO mice. By 9 months of age, P301S mice with different ApoE genotypes display distinct p-tau staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity following LPS treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of TNFα secretion and markedly reduced neuronal viability compared to neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNFα. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared to the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In Aβ-pathology positive individuals with symptomatic AD who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independent of Aβ pathology. ApoE4 exerts a “toxic” gain of function whereas the absence of ApoE is protective.

Hypercholesterolemia is a risk factor for estrogen receptor (ER) positive breast cancers and is associated with a decreased response of tumors to endocrine therapies. Here we show that 27-Hydroxycholesterol (27HC), a primary metabolite of cholesterol and an ER and Liver X receptor (LXR) ligand, increases ER-dependent growth and LXR-dependent metastasis in mouse models of breast cancer. The effects of cholesterol on tumor pathology required its conversion to 27HC by the cytochrome P450 oxidase CYP27A1, and were attenuated by treatment with CYP27A1 inhibitors. In human breast cancer specimens, CYP27A1 expression levels correlated with tumor grade. In high-grade tumors, both tumor cells and tumor-associated macrophages exhibited high expression levels of the enzyme. Thus, lowering circulating cholesterol levels or interfering with its conversion to 27HC may be a useful strategy to prevent and/or treat breast cancer.

Apolipoprotein (apo) E, a constituent of several lipoproteins, is a ligand for the low density lipoprotein receptor, and this interaction is important for maintaining cholesterol and triglyceride homeostasis. We have used a gene replacement strategy to generate mice that express the human apoE3 isoform in place of the mouse protein. The levels of apoE mRNA in various tissues are virtually the same in the human apoE3 homozygous (3/3) mice and their littermates having the wild type mouse allele (؉/؉). Total cholesterol and triglyceride levels in fasted plasma from the 3/3 mice were not different from those in the ؉/؉ mice, when maintained on a normal (low fat) chow diet. We found, however, notable differences in the distribution of plasma lipoproteins and apolipoprotein E between the two groups: ␤-migrating lipoproteins and plasma apoB100 levels are decreased in the 3/3 mice, and the apoE distribution is shifted from high density lipoproteins to larger lipoprotein particles. In addition, the fractional catabolic rate of exogenously administered remnant particles without apoE was 6-fold slower in the 3/3 mice compared with the ؉/؉ mice. When the 3/3 and ؉/؉ animals were fed a high fat/high cholesterol diet, the 3/3 animals responded with a dramatic increase (5-fold) in total cholesterol compared with the ؉/؉ mice (1.5-fold), and after 12 weeks on this same diet the 3/3 animals developed significantly (at least 13-fold) larger atherosclerotic plaques in the aortic sinus area than the ؉/؉ animals. Thus the structural differences between human APOE3 and mouse ApoE proteins are sufficient to cause an increased susceptibility to dietary-induced hypercholesterolemia and atherosclerosis in the 3/3 mice.

The androgen receptor (AR) mediates the actions of male sex steroids. Human AR genomic DNA was cloned from a flow-sorted human X chromosome library by using a consensus nucleotide sequence from the DNA-binding domain of the family of nuclear receptors. The AR gene was localized on the human X chromosome between the centromere and q13. Cloned complementary DNA, selected with an AR-specific oligonucleotide probe, was expressed in monkey kidney (COS) cells and yielded a high-affinity androgen-binding protein with steroid-binding specificity corresponding to that of native AR. A predominant messenger RNA species of 9.6 kilobases was identified in human, rat, and mouse tissues known to contain AR and was undetectable in tissues lacking AR androgen-binding activity, including kidney and liver from androgen-insensitive mice. The deduced amino acid sequence of AR within the DNA-binding domain has highest sequence identity with the progesterone receptor.

Human apolipoprotein E is the major apolipoprotein expressed in the brain and exists as three isoforms, designated E2, E3, and E4. Although evidence suggests that apolipoprotein E plays an important role in modifying systemic and brain inflammatory responses, there is little data investigating apoE isoform-specific effects in vivo. In this study, we compared the inflammatory responses of targeted-replacement mice expressing the human APOE3 and APOE4 genes after intravenous administration of lipopolysaccharide. Animals expressing the E4 allele had significantly greater systemic and brain elevations of the pro-inflammatory cytokines TNFalpha and IL-6 as compared with their APOE3 counterparts, suggesting an isoform-specific effect of the immunomodulatory properties of apoE. Furthermore, intravenous administration of a small apoE-mimetic peptide derived from the receptor-binding region of the apoE holoprotein (apoE-(133-149)) similarly suppressed both systemic and brain inflammatory responses in mice after lipopolysaccharide administration. These results suggest that apoE plays an isoform-specific role in mediating the systemic and brain inflammatory responses. Moreover, because exogenous administration of this apoE mimetic peptide is effective at suppressing both systemic and brain inflammation, it may represent a novel therapeutic strategy for diseases characterized by systemic or central nervous system inflammation, such as septic shock, multiple sclerosis, and traumatic brain injury.