Thomas Riya, Morris Alan W J, Tai Leon M
Department of Anatomy and Cell Biology, University of Illinois, Chicago, IL 60612, USA.
Heliyon. 2017 Jun 7;3(6):e00319. doi: 10.1016/j.heliyon.2017.e00319. eCollection 2017 Jun.
Cerebrovascular dysfunction is re-emerging as a major component of aging, and may contribute to the risk of developing Alzheimer's disease (AD). Two important risk factors for cerebrovascular dysfunction are and female sex, which are primarily researched in the context of high amyloid-β (Aβ) levels as found in AD. However, and sex modulate Aβ-independent pathways that may induce cerebrovascular dysfunction as a downstream consequence. Therefore, testing the activity of factors that target cerebrovascular dysfunction in Aβ-independent models that incorporate and female sex is crucial. We have previously demonstrated that peripheral administration of the epidermal growth factor (EGF) prevents cognitive dysfunction, cerebrovascular leakiness, and cerebrovascular coverage deficits in female mice that express and overproduce Aβ, without affecting Aβ levels. These data raise the question of whether EGF protects the cerebrovasculature from general stress-induced damage. Therefore, the goal of this study was to determine whether EGF prevents Aβ-independent cerebrovascular dysfunction. In eight-month old mice that express human , the interaction of and female sex induced cognitive dysfunction, increased cerebrovascular leakiness and lowered vessel coverage. Importantly, in a prevention paradigm (from six to eight and a half months of age), EGF ameliorated cognitive decline and cerebrovascular deficits in female mice that express . Thus, developing treatment strategies based on EGF signaling could provide alternative therapeutic options for age-related cerebrovascular dysfunction and reduce AD risk.
脑血管功能障碍正再次成为衰老的一个主要组成部分，并可能导致患阿尔茨海默病（AD）的风险增加。脑血管功能障碍的两个重要风险因素是[此处原文缺失相关内容]和女性性别，它们主要是在AD中发现的高淀粉样β蛋白（Aβ）水平的背景下进行研究的。然而，[此处原文缺失相关内容]和性别会调节不依赖Aβ的途径，这些途径可能会作为下游结果诱发脑血管功能障碍。因此，在纳入[此处原文缺失相关内容]和女性性别的不依赖Aβ的模型中测试针对脑血管功能障碍的因素的活性至关重要。我们之前已经证明，表皮生长因子（EGF）的外周给药可预防表达并过量产生Aβ的雌性小鼠的认知功能障碍、脑血管渗漏和脑血管覆盖缺陷，而不影响Aβ水平。这些数据提出了一个问题，即EGF是否能保护脑血管免受一般应激诱导的损伤。因此，本研究的目的是确定EGF是否能预防不依赖Aβ的脑血管功能障碍。在表达人类[此处原文缺失相关内容]的八个月大的小鼠中，[此处原文缺失相关内容]和女性性别的相互作用诱发了认知功能障碍、脑血管渗漏增加和血管覆盖率降低。重要的是，在一个预防范式（从六个月到八个半月大）中，EGF改善了表达[此处原文缺失相关内容]的雌性小鼠的认知衰退和脑血管缺陷。因此，基于EGF信号通路开发治疗策略可为与年龄相关的脑血管功能障碍提供替代治疗选择，并降低AD风险。
