Loss of ovarian hormones is detrimental in early disease stages of mouse models of Alzheimer’s disease and multi-etiology dementia

Abstract Background Up to 80% of Alzheimer’s disease (AD) patients suffer from brain vascular damage resulting in multi-etiology dementia (MED). Sex is a well-known risk factor for dementia; out of three AD patients two are women. 17β-estradiol, a predominant ovarian hormone in woman before menopause, is known to have beneficial effects on the cerebrovasculature, neuroinflammation and neuroprotection. Here, we investigated the consequences of the loss of ovarian hormones caused by surgical menopause (ovariectomy) on AD and MED. Methods The AppNL−F knock-in mice were used to model AD. At about 5.5 months of age, a stage corresponding to early disease pathology, female AppNL−F mice were subjected to ovariectomy (OVX) or sham surgery (Intact) and left to recover for 3 weeks to clear any endogenous gonadal hormones. In half of the mice from each group, MED was modeled using chronic cerebral hypoperfusion (unilateral carotid artery occlusion), a model of vascular contributions to cognitive impairment and dementia (VCID). Control animals (AD only model) received sham surgery. Mice were then subjected to a battery of behavioral tests before being euthanized and brains were collected to assess pathology. Results We found that loss of ovarian hormones impairs spatial learning and memory, impairs activities of daily living, and affects underlying pathology including compromising microglial response. Some of these effects were exacerbated by cerebral hypoperfusion (VCID). Conclusions These results shed light on the effects of ovarian hormone loss after surgical menopause in female mouse model of AD and MED in order to better understand sex-specific risk factors.