Sex differences in the effects of high fat diet on underlying neuropathology in a mouse model of VCID.
Sex differences in the effects of high fat diet on underlying neuropathology in a mouse model of VCID.
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DOI：
10.1186/s13293-023-00513-y
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发表时间：
2023-05-19
影响因子：
7.9
通讯作者：
中科院分区：
文献类型：
--
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脑血管受损可导致血管导致认知障碍和痴呆(VCID)。流向大脑的血流量减少会导致神经病理，包括神经炎症和脑白质损伤，这是VCID的特征。中年代谢性疾病(肥胖、糖尿病前期或糖尿病)是VCID的风险因素，VCID可能与性别有关(女性偏见)。我们比较了中年代谢性疾病在VCID慢性脑低灌注小鼠模型中的作用。C57BL/6J小鼠从8.5月龄~ 开始喂以对照或高脂(HF)饲料。饮食开始3个月后，行假手术或单侧颈动脉闭塞手术(VCID模型)。三个月后，小鼠接受了行为测试，并收集了大脑来评估病理。我们之前已经证明，在这个VCID模型中，与男性相比，HF饮食会导致女性更大的代谢损伤和更广泛的认知缺陷。在这里，我们报告了潜在的神经病理中的性别差异，特别是脑白质变化和大脑几个区域的神经炎症。男性的VCID和女性的HF饮食对白质产生了负面影响，只有女性的代谢受损与较少的髓鞘标志物相关。高脂饮食导致男性小胶质细胞激活增加，而女性则没有。此外，HF饮食导致女性的致炎细胞因子和促分解介质mRNA的表达减少，但男性没有。目前的研究增加了我们对存在共同危险因素(肥胖/糖尿病前期)的VCID潜在神经病理的性别差异的理解。这一信息对于开发针对VCID的有效的、针对性别的治疗干预措施至关重要。网上版载有补充材料，可在10.1186/s13293-023-00513-y查阅。血管受损导致的脑部血流量减少会导致血管性痴呆。神经炎症和脑白质损害是血管性痴呆的特征。中年是肥胖和糖尿病前期会增加患血管性痴呆风险的时期。这种风险的增加对女性来说更大。高脂肪饮食会导致小鼠肥胖和前驱糖尿病。我们在血管性痴呆的小鼠模型中比较了男性和女性在中年饮食诱导的肥胖的影响。我们之前已经证明，与男性相比，高脂肪饮食会导致女性更严重的肥胖和糖尿病前期，以及更广泛的学习和记忆问题。在这里，我们报告了大脑损伤中的性别差异。男性的血管性痴呆和女性的高脂肪饮食对白质有负面影响，只有女性的白质标记物较少与更严重的糖尿病前期相关。高脂肪饮食导致男性小胶质细胞(大脑中的免疫细胞)激活增加，但女性没有。高脂饮食还导致女性的促炎和促分解介质的表达减少，但男性没有。目前的研究增加了我们对存在共同危险因素(肥胖和糖尿病前期)的血管性痴呆对大脑潜在损害的性别差异的理解。这些信息是开发有效的、针对性别的血管性痴呆治疗方法所必需的。网上版载有补充材料，可在10.1186/s13293-023-00513-y查阅。男性大脑低灌注量和女性高脂肪饮食对脑白质有负面影响。高脂饮食导致男性小胶质细胞(Iba1+CD68+细胞)活化增加，而女性则无明显变化。在两性中，激活的小胶质细胞的增加与较差的间歇性记忆有关。高脂饮食导致雌性大鼠前炎症细胞因子和促分解因子的mRNA表达下降，而雄性大鼠则无明显变化。在患有VCID和代谢性疾病的小鼠模型中：在线版本包含可在10.1186/s13293-023-00513-y获得的补充材料。
Damage to the cerebral vasculature can lead to vascular contributions to cognitive impairment and dementia (VCID). A reduction in blood flow to the brain leads to neuropathology, including neuroinflammation and white matter lesions that are a hallmark of VCID. Mid-life metabolic disease (obesity, prediabetes, or diabetes) is a risk factor for VCID which may be sex-dependent (female bias). We compared the effects of mid-life metabolic disease between males and females in a chronic cerebral hypoperfusion mouse model of VCID. C57BL/6J mice were fed a control or high fat (HF) diet starting at ~ 8.5 months of age. Three months after diet initiation, sham or unilateral carotid artery occlusion surgery (VCID model) was performed. Three months later, mice underwent behavior testing and brains were collected to assess pathology. We have previously shown that in this VCID model, HF diet causes greater metabolic impairment and a wider array of cognitive deficits in females compared to males. Here, we report on sex differences in the underlying neuropathology, specifically white matter changes and neuroinflammation in several areas of the brain. White matter was negatively impacted by VCID in males and HF diet in females, with greater metabolic impairment correlating with less myelin markers in females only. High fat diet led to an increase in microglia activation in males but not in females. Further, HF diet led to a decrease in proinflammatory cytokines and pro-resolving mediator mRNA expression in females but not males. The current study adds to our understanding of sex differences in underlying neuropathology of VCID in the presence of a common risk factor (obesity/prediabetes). This information is crucial for the development of effective, sex-specific therapeutic interventions for VCID. The online version contains supplementary material available at 10.1186/s13293-023-00513-y. Reduced blood flow to the brain resulting from damaged blood vessels can lead to vascular dementia. Neuroinflammation and white matter damage are characteristics of vascular dementia. Middle-age is a time when obesity and prediabetes can increase risk for vascular dementia. This increase in risk is greater for women. A high fat diet causes obesity and prediabetes in mice. We compared the effects of diet-induced obesity in middle-age between males and females in a mouse model of vascular dementia. We have previously shown that a high fat diet causes greater obesity and prediabetes and a wider array of learning and memory problems in females compared to males. Here, we report on sex differences in the damage to the brain. White matter was negatively impacted by vascular dementia in males and high fat diet in females, with more severe prediabetes correlating with less white matter markers in females only. High fat diet led to an increase in activation of microglia (immune cells in the brain) in males but not in females. High fat diet also led to a decrease in pro-inflammatory and pro-resolving mediators expression in females but not males. The current study adds to our understanding of sex differences in underlying damage to the brain caused by vascular dementia in the presence of common risk factors (obesity and prediabetes). This information is needed for the development of effective, sex-specific treatments for vascular dementia. The online version contains supplementary material available at 10.1186/s13293-023-00513-y. White matter was negatively impacted by cerebral hypoperfusion in males and by high fat diet in females. High fat diet led to an increase in activation of microglial cells (Iba1+CD68+ cells) in males but not in females. In both sexes, an increase in activated microglia was associated with worse episodic-like memory. High fat diet led to a decrease in mRNA expression of proinflammatory cytokines and pro-resolving factors in females but not in males. In a mouse model of comorbid VCID and metabolic disease: The online version contains supplementary material available at 10.1186/s13293-023-00513-y.
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