Influence of Sex Hormones in a Mouse Model of Multi Etiology Dementia

Abstract

AbstractBackgroundUp to 80% of Alzheimer’s Disease (AD) patients suffer from concurrent vascular contributions to cognitive impairment and dementia (VCID) resulting in multi‐etiology dementia. VCID (the 2nd leading cause of dementia) is more common in men throughout most of the lifespan. while the majority (approximately 2/3) of Alzheimer’s Disease (AD) patients are women. Ageing is a main dementia risk factor which may act through the depletion of sex hormones. Both testosterone, in men, and estrogen, in women, have been shown to be neuroprotective. In this study we examine the effect of gonadal hormones on cognitive changes in a mouse model of multi etiology dementia using the AppNL‐F/NL‐F knock‐in Alzheimer’s disease mouse model that does not overexpress amyloid precursor protein.Methods5‐6 months old App NL‐F/NL‐F mice were subjected to gonadectomy or sham surgery and left to recover for 3 weeks to clear any endogenous gonadal hormones. Multi‐etiology dementia was modeled using chronic cerebral hypoperfusion (unilateral carotid artery occlusion). Control animals (App NL‐F/NL‐F without hypoperfusion; AD only model) received a sham surgery. Mice were then subjected to a battery of behavioral tests before being euthanized and then brains and serum were collected.ResultsCognitive impairment differences between groups were investigated using several behavioral tests: anxiety‐like behavior and activity levels using an open field testing, episodic‐like memory using a novel object recognition test, spatial learning and memory via Barnes maze testing and activities of daily living using a nest building test. Our next step is to evaluate the underlying pathology in the brain that could mediate cognitive deficits (i.e. amyloid pathology, white matter damage and neuroinflammation).ConclusionsWe hope that this work will highlight the importance of modeling endocrine aging in animal models of dementia and will contribute to further understanding of sex differences and sex specific risk factors for dementia.