Diabetes increases the risk of Alzheimer’s disease (AD). We investigated the impact of glucose concentrations on the β-amyloid (Aβ)-induced alteration of mitochondrial/cellular energetics in primary human brain microvascular endothelial cells (HBMECs). HBMECs were grown and passaged in media containing 15 mmol/l glucose (normal) based on which the glucose levels in the media were designated as high (25 mmol/L) or low (5 mmol/L). HBMECs were treated with Aβ (1–42) (5 µmol/l) or a scrambled peptide for 24 h and mitochondrial respiratory parameters were measured using Seahorse Mito Stress Test. Aβ (1–42) decreased the mitochondrial ATP production at normal glucose levels and decreased spare respiratory capacity at high glucose levels. Aβ (1–42) diminished all mitochondrial respiratory parameters markedly at low glucose levels that were not completely recovered by restoring normal glucose levels in the media. The addition of mannitol (10 mmol/l) to low and normal glucose-containing media altered the Aβ (1–42)-induced bioenergetic defects. Even at normal glucose levels, pre-senescent HMBECs (passage 15) displayed greater Aβ (1–42)-induced mitochondrial respiratory impairments than young cells (passages 7–9). Thus, hypoglycemia, osmolarity changes, and senescence are stronger instigators of Aβ (1–42)-induced mitochondrial respiration and energetics in HBMECs and contributors to diabetes-related increased AD risk than hyperglycemia.

糖尿病会增加患阿尔茨海默病 (AD) 的风险。我们研究了葡萄糖浓度对原代人脑微血管内皮细胞 (HBMEC) 中 β-淀粉样蛋白 (Aβ) 诱导的线粒体/细胞能量学改变的影响。 HBMEC 在含有 15 mmol/l 葡萄糖（正常）的培养基中生长和传代，根据培养基中的葡萄糖水平指定为高 (25 mmol/L) 或低 (5 mmol/L)。 HBMEC 用 Aβ (1–42) (5 µmol/l) 或乱序肽处理 24 小时，并使用 Seahorse Mito 压力测试测量线粒体呼吸参数。 Aβ (1-42) 在正常葡萄糖水平下会降低线粒体 ATP 的产生，在高葡萄糖水平下会降低备用呼吸能力。 Aβ (1-42) 在低葡萄糖水平下显着降低所有线粒体呼吸参数，但通过恢复培养基中的正常葡萄糖水平并不能完全恢复这些参数。在含低葡萄糖和正常葡萄糖的培养基中添加甘露醇 (10 mmol/l) 可以改变 Aβ (1-42) 诱导的生物能缺陷。即使在正常的葡萄糖水平下，衰老前的 HMBEC（第 15 代）也比年轻细胞（第 7-9 代）表现出更大的 Aβ (1-42) 诱导的线粒体呼吸损伤。因此，与高血糖相比，低血糖、渗透压变化和衰老是 Aβ (1-42) 诱导的 HBMEC 线粒体呼吸和能量学的更强刺激因素，也是导致糖尿病相关 AD 风险增加的因素。