Evidence associates cardiovascular risk factors with unfavorable systemic and neuro-inflammation and cognitive decline in the elderly. Cardiovascular therapeutics (e.g., statins and anti-hypertensives) possess immune-modulatory functions in parallel to their cholesterol- or blood pressure (BP)-lowering properties. How their ability to modify immune responses affects cognitive function is unknown. Here, we examined the effect of chronic hypercholesterolemia on inflammation and memory function in Apolipoprotein E (ApoE) knockout mice and normocholesterolemic wild-type mice. Chronic hypercholesterolemia that was accompanied by moderate blood pressure elevations associated with apparent immune system activation characterized by increases in circulating pro-inflammatory Ly6Chi monocytes in ApoE-/- mice. The persistent low-grade immune activation that is associated with chronic hypercholesterolemia facilitates the infiltration of pro-inflammatory Ly6Chi monocytes into the brain of aged ApoE-/- but not wild-type mice, and links to memory dysfunction. Therapeutic cholesterol-lowering through simvastatin reduced systemic and neuro-inflammation, and the occurrence of memory deficits in aged ApoE-/- mice with chronic hypercholesterolemia. BP-lowering therapy alone (i.e., hydralazine) attenuated some neuro-inflammatory signatures but not the occurrence of memory deficits. Our study suggests a link between chronic hypercholesterolemia, myeloid cell activation and neuro-inflammation with memory impairment and encourages cholesterol-lowering therapy as safe strategy to control hypercholesterolemia-associated memory decline during ageing.

中文翻译：

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辛伐他汀治疗减轻与慢性高胆固醇血症脑单核细胞浸润相关的记忆缺陷

证据表明，心血管危险因素与老年人不利的全身和神经炎症以及认知能力下降有关。心血管疗法（例如，他汀类药物和抗高血压药）具有免疫调节功能，同时具有降低胆固醇或血压 (BP) 的特性。他们改变免疫反应的能力如何影响认知功能尚不清楚。在这里，我们检查了慢性高胆固醇血症对载脂蛋白 E (ApoE) 敲除小鼠和正常胆固醇野生型小鼠的炎症和记忆功能的影响。慢性高胆固醇血症伴随着与明显的免疫系统激活相关的中度血压升高，其特征是 ApoE-/- 小鼠中循环促炎性 Ly6Chi 单核细胞的增加。与慢性高胆固醇血症相关的持续低级别免疫激活促进了促炎性 Ly6Chi 单核细胞渗入老年 ApoE-/- 但不是野生型小鼠的大脑，并与记忆功能障碍有关。通过辛伐他汀降低胆固醇的治疗性降低全身和神经炎症，以及患有慢性高胆固醇血症的老年 ApoE-/- 小鼠记忆缺陷的发生。单独的降压疗法（即肼苯哒嗪）可以减轻一些神经炎症特征，但不能减轻记忆缺陷的发生。我们的研究表明慢性高胆固醇血症、骨髓细胞活化和神经炎症与记忆障碍之间存在联系，并鼓励降低胆固醇治疗作为控制衰老期间高胆固醇血症相关记忆力下降的安全策略。