Department of Neuroscience & Experimental Therapeutics, Albany Medical College, Albany, NY, USA.
Department of Psychology and Center for Neuroscience Research, State University of New York at Albany, Albany, NY, USA.
J Alzheimers Dis. 2024;101(4):1177-1194. doi: 10.3233/JAD-231332.
About two-thirds of those with Alzheimer's disease (AD) are women, most of whom are post-menopausal. Menopause accelerates dementia risk by increasing the risk for metabolic, cardiovascular, and cerebrovascular diseases. Mid-life metabolic disease (obesity, diabetes/prediabetes) is a well-known risk factor for dementia. A high fat diet can lead to poor metabolic health in both humans and rodents.
Our goal was to determine the effects of a high fat diet on metabolic outcomes in the AppNL-F knock-in mouse model of AD and assess the effects of menopause.
First, 3-month-old AppNL-F and WT female mice were placed on either a control or a high fat diet until 10 months of age then assessed for metabolic outcomes. Next, we did a more extensive assessment in AppNL-F mice that were administered VCD (4-vinylcyclohexene diepoxide) or vehicle (oil) and placed on a control or high fat diet for 7 months. VCD was used to model menopause by causing accelerated ovarian failure.
Compared to WT controls, AD female mice had worse glucose intolerance. Menopause led to metabolic impairment (weight gain and glucose intolerance) and further exacerbated obesity in response to a high fat diet. There were interactions between diet and menopause on some metabolic health serum biomarkers and the expression of hypothalamic markers related to energy balance.
This work highlights the need to model endocrine aging in animal models of dementia and will contribute to further understanding the interaction between menopause and metabolic health in the context of AD.
大约三分之二的阿尔茨海默病（AD）患者为女性，其中大多数处于绝经后状态。绝经会增加代谢、心血管和脑血管疾病的风险，从而加速痴呆的风险。中年期代谢疾病（肥胖、糖尿病/糖尿病前期）是痴呆的已知危险因素。高脂肪饮食会导致人类和啮齿动物的代谢健康状况不佳。
我们的目标是确定高脂肪饮食对 AD 模型 AppNL-F 敲入小鼠代谢结果的影响，并评估绝经的影响。
首先，将 3 月龄 AppNL-F 和 WT 雌性小鼠分别置于对照或高脂肪饮食中，直至 10 个月大，然后评估代谢结果。接下来，我们在 AppNL-F 小鼠中进行了更广泛的评估，这些小鼠接受了 VCD（4-乙烯基环己烯二环氧化物）或载体（油），并置于对照或高脂肪饮食中 7 个月。VCD 通过导致卵巢早衰来模拟绝经。
与 WT 对照组相比，AD 雌性小鼠的葡萄糖耐量更差。绝经导致代谢损伤（体重增加和葡萄糖耐量受损），并在高脂肪饮食下进一步加剧肥胖。饮食和绝经对一些代谢健康血清生物标志物和与能量平衡相关的下丘脑标志物的表达有交互作用。
这项工作强调了在痴呆动物模型中模拟内分泌衰老的必要性，并将有助于进一步了解绝经和代谢健康在 AD 背景下的相互作用。
