Department of Cellular and Integrative Physiology and Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio , San Antonio, Texas.
Department of Neurosurgery, University of Texas Health San Antonio , San Antonio, Texas.
Am J Physiol Heart Circ Physiol. 2018 Apr 1;314(4):H693-H703. doi: 10.1152/ajpheart.00570.2017. Epub 2017 Dec 22.
An intact blood-brain barrier (BBB) limits entry of proinflammatory and neurotoxic blood-derived factors into the brain parenchyma. The BBB is damaged in Alzheimer's disease (AD), which contributes significantly to the progression of AD pathologies and cognitive decline. However, the mechanisms underlying BBB breakdown in AD remain elusive, and no interventions are available for treatment or prevention. We and others recently established that inhibition of the mammalian/mechanistic target of rapamycin (mTOR) pathway with rapamycin yields significant neuroprotective effects, improving cerebrovascular and cognitive function in mouse models of AD. To test whether mTOR inhibition protects the BBB in neurological diseases of aging, we treated hAPP(J20) mice modeling AD and low-density lipoprotein receptor-null (LDLR) mice modeling vascular cognitive impairment with rapamycin. We found that inhibition of mTOR abrogates BBB breakdown in hAPP(J20) and LDLR mice. Experiments using an in vitro BBB model indicated that mTOR attenuation preserves BBB integrity through upregulation of specific tight junction proteins and downregulation of matrix metalloproteinase-9 activity. Together, our data establish mTOR activity as a critical mediator of BBB breakdown in AD and, potentially, vascular cognitive impairment and suggest that rapamycin and/or rapalogs could be used for the restoration of BBB integrity. NEW & NOTEWORTHY This report establishes mammalian/mechanistic target of rapamycin as a critical mediator of blood-brain barrier breakdown in models of Alzheimer's disease and vascular cognitive impairment and suggests that drugs targeting the target of rapamycin pathway could be used for the restoration of blood-brain barrier integrity in disease states.
完整的血脑屏障（BBB）限制了促炎和神经毒性的血液来源因子进入脑实质。阿尔茨海默病（AD）会损害血脑屏障，这对 AD 病理和认知能力下降的进展有重大影响。然而，AD 中血脑屏障破坏的机制仍不清楚，也没有可用于治疗或预防的干预措施。我们和其他人最近发现，用雷帕霉素抑制哺乳动物/机械靶标雷帕霉素（mTOR）通路可产生显著的神经保护作用，改善 AD 小鼠模型的脑血管和认知功能。为了测试 mTOR 抑制是否能保护衰老相关神经疾病中的血脑屏障，我们用雷帕霉素治疗了模拟 AD 的 hAPP（J20）小鼠和模拟血管性认知障碍的低密度脂蛋白受体缺失（LDLR）小鼠。我们发现，mTOR 抑制可消除 hAPP（J20）和 LDLR 小鼠的血脑屏障破坏。使用体外血脑屏障模型的实验表明，mTOR 衰减通过上调特定的紧密连接蛋白和下调基质金属蛋白酶-9 活性来维持血脑屏障的完整性。总之，我们的数据表明 mTOR 活性是 AD 中血脑屏障破坏的关键介质，并且可能是血管性认知障碍，并表明雷帕霉素和/或 rapalog 可用于恢复血脑屏障的完整性。新的和值得注意的是，本报告将哺乳动物/机械靶标雷帕霉素确立为阿尔茨海默病和血管性认知障碍模型中血脑屏障破坏的关键介质，并表明靶向雷帕霉素通路的药物可用于在疾病状态下恢复血脑屏障的完整性。
