Barshop Institute for Longevity and Aging Studies, Department of Cellular and Integrative Physiology, University of Texas Health San Antonio, San Antonio, Texas 78229.
The Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health San Antonio, San Antonio, Texas 78229.
J Neurosci. 2021 May 12;41(19):4305-4320. doi: 10.1523/JNEUROSCI.2144-20.2021. Epub 2021 Apr 22.
Vascular dysfunction is a universal feature of aging and decreased cerebral blood flow has been identified as an early event in the pathogenesis of Alzheimer's disease (AD). Cerebrovascular dysfunction in AD includes deficits in neurovascular coupling (NVC), a mechanism that ensures rapid delivery of energy substrates to active neurons through the blood supply. The mechanisms underlying NVC impairment in AD, however, are not well understood. We have previously shown that mechanistic/mammalian target of rapamycin (mTOR) drives cerebrovascular dysfunction in models of AD by reducing the activity of endothelial nitric oxide synthase (eNOS), and that attenuation of mTOR activity with rapamycin is sufficient to restore eNOS-dependent cerebrovascular function. Here we show mTOR drives NVC impairments in an AD model through the inhibition of neuronal NOS (nNOS)- and non-NOS-dependent components of NVC, and that mTOR attenuation with rapamycin is sufficient to restore NVC and even enhance it above WT responses. Restoration of NVC and concomitant reduction of cortical amyloid-β levels effectively treated memory deficits in 12-month-old hAPP(J20) mice. These data indicate that mTOR is a critical driver of NVC dysfunction and underlies cognitive impairment in an AD model. Together with our previous findings, the present studies suggest that mTOR promotes cerebrovascular dysfunction in AD, which is associated with early disruption of nNOS activation, through its broad negative impact on nNOS as well as on non-NOS components of NVC. Our studies highlight the potential of mTOR attenuation as an efficacious treatment for AD and potentially other neurologic diseases of aging. Failure of the blood flow response to neuronal activation [neurovascular coupling (NVC)] in a model of AD precedes the onset of AD-like cognitive symptoms and is driven, to a large extent, by mammalian/mechanistic target of rapamycin (mTOR)-dependent inhibition of nitric oxide synthase activity. Our studies show that mTOR also drives AD-like failure of non-nitric oxide (NO)-mediated components of NVC. Thus, mTOR attenuation may serve to treat AD, where we find that neuronal NO synthase is profoundly reduced early in disease progression, and potentially other neurologic diseases of aging with cerebrovascular dysfunction as part of their etiology.
血管功能障碍是衰老的普遍特征，并且已经发现脑血流减少是阿尔茨海默病（AD）发病机制中的早期事件。AD 中的脑血管功能障碍包括神经血管耦联（NVC）缺陷，这是一种通过血液供应向活跃神经元快速输送能量底物的机制。然而，AD 中 NVC 损伤的机制尚不清楚。我们之前已经表明，机械/哺乳动物雷帕霉素靶蛋白（mTOR）通过降低内皮型一氧化氮合酶（eNOS）的活性来驱动 AD 模型中的脑血管功能障碍，并且用雷帕霉素减弱 mTOR 活性足以恢复 eNOS 依赖性脑血管功能。在这里，我们表明 mTOR 通过抑制神经元型一氧化氮合酶（nNOS）和 NVC 的非-NOS 依赖成分来驱动 AD 模型中的 NVC 损伤，并且用雷帕霉素减弱 mTOR 活性足以恢复 NVC，甚至使其增强超过 WT 反应。NVC 的恢复以及皮质淀粉样蛋白-β水平的同时降低有效地治疗了 12 个月大的 hAPP（J20）小鼠的记忆缺陷。这些数据表明 mTOR 是 NVC 功能障碍的关键驱动因素，也是 AD 模型中认知障碍的基础。结合我们之前的发现，本研究表明 mTOR 通过其对 nNOS 以及 NVC 的非-NOS 成分的广泛负面影响，促进 AD 中的脑血管功能障碍，这与 nNOS 激活的早期破坏有关。我们的研究强调了减弱 mTOR 作为 AD 及其他神经退行性疾病有效治疗方法的潜力。在 AD 模型中，对神经元激活的血流反应（神经血管耦联（NVC））的失败先于 AD 样认知症状的发作，并且在很大程度上受到哺乳动物/机械雷帕霉素靶蛋白（mTOR）依赖性一氧化氮合酶活性抑制的驱动。我们的研究表明，mTOR 还驱动 AD 样非一氧化氮（NO）介导的 NVC 成分的失败。因此，减弱 mTOR 可能有助于治疗 AD，我们发现神经元一氧化氮合酶在疾病进展的早期就明显减少，并且可能有助于治疗其他具有脑血管功能障碍的神经退行性疾病，这些疾病的病因部分与它们有关。
