Diabetes mellitus (DM) is a leading risk factor for aging-related dementia; however, the underlying mechanisms are not well understood. The present study, utilizing a non-obese T2DN diabetic model, demonstrates that the myogenic response of the middle cerebral artery (MCA) and parenchymal arteriole (PA) and autoregulation of cerebral blood flow (CBF) in the surface and deep cortex were impaired at both young and old ages. The impaired CBF autoregulation was more severe in old than young DM rats, and in the deep than the surface cortex. The myogenic tone of the MCA was enhanced at perfusion pressure in the range of 40–100 mmHg in young DM rats but was reduced at 140–180 mmHg in old DM rats. No change of the myogenic tone of the PA was observed in young DM rats, whereas it was significantly reduced at 30–60 mmHg in old DM rats. Old DM rats had enhanced blood-brain barrier (BBB) leakage and neurodegeneration, reduced vascular density, tight junction, and pericyte coverage on cerebral capillaries in the CA3 region in the hippocampus. Additionally, DM rats displayed impaired functional hyperemia and spatial learning and short- and long-term memory at both young and old ages. Old DM rats had impaired non-spatial short-term memory. These results revealed that impaired CBF autoregulation and enhanced BBB leakage plays an essential role in the pathogenesis of age- and diabetes-related dementia. These findings will lay the foundations for the discovery of anti-diabetic therapies targeting restoring CBF autoregulation to prevent the onset and progression of dementia in elderly DM.

糖尿病（DM）是与衰老相关的痴呆症的主要危险因素。但是，潜在的机制还没有被很好地理解。本研究利用非肥胖型T2DN糖尿病模型，证明在表皮和深层皮层中，大脑中动脉（MCA）和实质小动脉（PA）的成肌反应以及脑血流量（CBF）的自动调节受到损害。不论男女老少。与年轻的DM大鼠相比，老年的CBF自动调节受损更为严重，而在深部则高于表面皮质。在年轻的DM大鼠中，在40-100 mmHg的灌注压力下，MCA的肌原性增强，而在老的DM大鼠中，MCA的肌原性在140-180 mmHg的情况下降低。在年轻的DM大鼠中，未观察到PA的肌原性变化，而在老的DM大鼠中，PA在30–60 mmHg时显着降低。老年DM大鼠在海马CA3区的脑毛细血管上具有增强的血脑屏障（BBB）泄漏和神经变性，降低的血管密度，紧密的连接以及周细胞覆盖。此外，DM大鼠在年轻人和老年人中均显示出功能性充血和空间学习受损以及短期和长期记忆。老年DM大鼠的非空间短期记忆受损。这些结果表明，CBF的自动调节功能受损和BBB渗漏增强在与年龄和糖尿病相关的痴呆症的发病机理中起着至关重要的作用。这些发现将为发现针对糖尿病的抗糖尿病疗法的基础，该疗法旨在恢复CBF的自动调节以预防老年痴呆症的发生和发展。以及海马CA3区脑毛细血管的周细胞覆盖。此外，DM大鼠在年轻人和老年人中均显示出功能性充血和空间学习受损以及短期和长期记忆。老年DM大鼠的非空间短期记忆受损。这些结果表明，CBF的自动调节功能受损和BBB渗漏增强在与年龄和糖尿病相关的痴呆症的发病机理中起着至关重要的作用。这些发现将为发现针对糖尿病的抗糖尿病疗法的基础，该疗法旨在恢复CBF的自动调节以预防老年痴呆症的发生和发展。以及海马CA3区脑毛细血管的周细胞覆盖。此外，DM大鼠在年轻人和老年人中均显示出功能性充血和空间学习受损以及短期和长期记忆。老年DM大鼠的非空间短期记忆受损。这些结果表明，CBF的自动调节功能受损和BBB渗漏增强在与年龄和糖尿病相关的痴呆症的发病机理中起着至关重要的作用。这些发现将为发现针对糖尿病的抗糖尿病疗法的基础，该疗法旨在恢复CBF的自动调节以预防老年痴呆症的发生和发展。DM大鼠在年轻人和老年人中均显示出功能性充血和空间学习受损以及短期和长期记忆。老年DM大鼠的非空间短期记忆受损。这些结果表明，CBF的自动调节受损和BBB渗漏的增加在与年龄和糖尿病相关的痴呆症的发病机理中起着至关重要的作用。这些发现将为发现针对糖尿病的抗糖尿病疗法的基础，该疗法旨在恢复CBF的自动调节以预防老年痴呆症的发生和发展。DM大鼠在年轻人和老年人中均显示出功能性充血和空间学习受损以及短期和长期记忆。老年DM大鼠的非空间短期记忆受损。这些结果表明，CBF的自动调节受损和BBB渗漏的增加在与年龄和糖尿病相关的痴呆症的发病机理中起着至关重要的作用。这些发现将为发现针对糖尿病的抗糖尿病疗法的基础，该疗法旨在恢复CBF的自动调节以预防老年痴呆症的发生和发展。