Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging/Center for Geroscience and Healthy Brain Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
International Training Program in Geroscience, Institute of Biophysics, Biological Research Centre, Szeged, Hungary.
Geroscience. 2020 Dec;42(6):1685-1698. doi: 10.1007/s11357-020-00256-3. Epub 2020 Aug 25.
Clinical studies show that cerebral amyloid angiopathy (CAA) associated with Alzheimer's disease (AD) and arterial hypertension are independent risk factors for cerebral microhemorrhages (CMHs). To test the hypothesis that amyloid pathology and hypertension interact to promote the development of CMHs, we induced hypertension in the Tg2576 mouse model of AD and respective controls by treatment with angiotensin II (Ang II) and the NO synthesis inhibitor L-NAME. The number, size, localization, and neurological consequences (gait alterations) of CMHs were compared. We found that compared to control mice, in TG2576 mice, the same level of hypertension led to significantly increased CMH burden and exacerbation of CMH-related gait alterations. In hypertensive TG2576 mice, CMHs were predominantly located in the cerebral cortex at the cortical-subcortical boundary, mimicking the clinical picture seen in patients with CAA. Collectively, amyloid pathologies exacerbate the effects of hypertension, promoting the genesis of CMHs, which likely contribute to their deleterious effects on cognitive function. Therapeutic strategies for prevention of CMHs that reduce blood pressure and preserve microvascular integrity are expected to exert neuroprotective effects in high-risk elderly AD patients.
临床研究表明，与阿尔茨海默病（AD）相关的脑淀粉样血管病（CAA）和动脉高血压是脑微出血（CMHs）的独立危险因素。为了验证淀粉样蛋白病理和高血压相互作用促进 CMHs 发展的假说，我们通过用血管紧张素 II（Ang II）和一氧化氮合酶抑制剂 L-NAME 处理 AD 的 Tg2576 小鼠模型和各自的对照来诱导高血压。比较 CMHs 的数量、大小、定位和神经学后果（步态改变）。我们发现，与对照小鼠相比，在 TG2576 小鼠中，相同水平的高血压导致 CMH 负担显著增加，并且 CMH 相关的步态改变恶化。在高血压 TG2576 小鼠中，CMHs 主要位于皮质下边界的大脑皮层，模拟了在 CAA 患者中看到的临床图像。总之，淀粉样蛋白病变加重了高血压的影响，促进了 CMHs 的发生，这可能对认知功能产生有害影响。预计降低血压和保持微血管完整性的预防 CMHs 的治疗策略将对高风险老年 AD 患者发挥神经保护作用。
