Impact of APOE4 on gender-specific mechanism for Alzheimer's disease

Even though so many risk factors and the related hypotheses for Alzheimer’s disease (AD) have been proposed, the exact disease-modifying therapies have not been established. The female predominance in the development of AD also has been well demonstrated as a risk factor. Therefore, understanding sex-specific differences in AD and identifying the underlying mechanisms are important for the treatment and intervention of sex-related AD. It is well known that Apolipoprotein E4 (APOE4) is a major genetic risk factor for developing late-onset AD. Furthermore, there is a correlation between APOE4 and cognitive decline in older women. However, the molecular mechanism responsible for the female prevalence of AD and the exact relevance of APOE4 in sex differences in AD remain unclear. Currently, many APOE4 and sex-specific biological researches of AD highlight the association with sex hormone, estrogen. On the contrary, we recently discovered that follicle-stimulating hormone (FSH), which is sharply escalated in women with menopause, accelerates AD pathologies in women via activating the pathological C/EBP/-secretase signaling for AD that we revealed in the recent study and blockade of FSH improves cognition in AD mice, suggesting that FSH is the driving factor for AD. Moreover, we observed that APOE4 also promotes C/EBP/-secretase signaling in neurons as FSH does. The goal of this proposal is to investigate the associative role of the AD risk gene, APOE4, and menopause-related hormone, FSH, in the initiation and progression of AD. Therefore, we will explore whether APOE4 is implicated in facilitating AD pathology in women, especially related to FSH-induced mechanisms. In addition, we will examine whether APOE4 mediates Tau propagation through low-density lipoprotein receptor (LDLR) and microglial-induced inflammation with FSH, and subsequently facilitate the progression of AD sex-differently because FSH also modulates the activity of LDLR and microglial inflammatory signaling via C/EBP. Lastly, we will test the synergistic therapeutic effect of the recombinant human APOE3 R136S protein, which is a protective mutation of APOE, and FSH antibody employing APOE4- and FSH-mediated AD mice model of ovariectomized (OVX)-APOE4 TR mice. Successful completion of this proposal will provide insight into the roles of APOE4 and FSH as novel molecular mechanisms underlying the sex-dependent AD progression. In addition, the expected results will present a new therapeutic strategy for the intervention and prevention of AD.