| Alzheimer's disease (AD), the most common form of dementia, is a devastating progressive neurodegenerative disease that currently remains incurable. Epidemiological studies indicate that AD disproportionally affects more women than men; among the elderly (≥65 years), the ratio for this discrepancy rises to nearly 2:1. AD patients who are women also experience earlier and more pronounced AD pathology than do men. The increased prevalence and severity of AD in women is strongly associated with age-related ovarian hormone loss and the apolipoprotein E 4 allele (ApoE4), the most important genetic risk factor for sporadic AD. ApoE4 not only exacerbates AD progression in women, but also compromises the effectiveness of estrogen-based hormone therapy (HT) in improving cognitive function among postmenopausal women. However, the underlying mechanism of how ApoE4 and estrogen interact to contribute to the development of AD remain unclear.;First, to evaluate contributions of ApoE4 within sex-dependent AD progression, we used two mouse models for AD: mice bearing three familial AD mutations (APPswe, PS1M146V, taup301L, 3xTg) and 3xTg mice with the human ApoE4 allele (ApoE4/3xTg). The transgenic mice were compared with age- and sex-matched nonTg control mice of the same genetic backgrounds. As compared to these controls, both 3xTg and ApoE4/3xTg mice exhibited hippocampus-dependent learning and memory deficits in the behavioral tests. However, mid-aged female ApoE4/3xTg mice, as compared to males, demonstrated an earlier appearance and greater severity of these deficits. Further, the deficits were associated with two important changes in hippocampal tissue: increased Abeta depositions, a major AD pathological hallmark, and increased BACE1 protein expression and enzymatic activity (BACE 1 is critical for Abeta production). Finally, BACE1 protein expression was significantly correlated with the expression of transcription factor Sp l , with higher BACE1 and Sp1 levels noted in female ApoE4/3xTg mice. All these findings for female mice were observed at the age when irregular estrous usually begins.;Second, to elucidate the contribution of ovarian hormones to AD development, we compared behavioral outcomes and AD neuropathology in sham and ovariectomized (OVX, a model of acute surgical ovarian hormone depletion) female ApoE4/3xTg mice, with sham and OVX nonTg mice as controls. Numerous studies report the neuroprotective actions of estrogen on various aspects of AD pathology. Many of these actions, particularly those involving cognition and mood, are mediated through estrogen receptor (ER) beta. Thus OVX mice were treated with either 17beta-estradiol (E2), an agonist for both ERalpha and ERbeta, or DPN, an ERbeta specific agonist, to study the effect of each in learning and memory. In our results, OVX ApoE4/3xTg mice showed more severe learning and memory deficits than did sham controls. No OVX effect was observed in nonTg mice. In the hippocampus of both sham and OVX ApoE4/3xTg mice, amyloid precursor protein (APP), Abeta and BACE 1 protein expressions were significantly increased, and OVX further elevated these levels. Treatment with DPN, but not with E2, successfully improved learning and memory of OVX ApoE4/3xTg mice as measured by two behavioral tests.;Third, we sought to investigate any sex-dependent effect of the ApoE4 domain interaction occurring between its N- and C-terminals in AD development. Mice with a point mutation replacing Threonine with Arginine at position 61 (Arg-61) were compared by sex and by sham vs. OVX. All experimental groups were also compared to age- and sex-matched C57BL/6J background mice. Similar to ApoE4/3xTg mice, female Arg-61 mice showed more severe learning and memory deficits, higher BACE1 expressions and increased neurodegeneration in the hippocampus, with OVX further exacerbating cognitive deficits.;The results of our assessment of cognitive deficits and brain pathology suggest that ApoE4, and especially its domain interaction, plays a pivotal role in the sex-dependent development of AD. These findings provide potential therapeutic strategies for AD therapy in females. |
