Millien Guetchyn, Wang Huaixing, Zhang Zongxiu, Alkon Dan L, Hongpaisan Jarin
Center for Translational Medicine, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States.
Neurotrope Bioscience, Inc., New York, NY, United States.
Front Aging Neurosci. 2022 Mar 1;14:836634. doi: 10.3389/fnagi.2022.836634. eCollection 2022.
Vascular endothelial dysfunction and capillary loss are currently considered to be a primary phenotype of normal human aging and Alzheimer's disease (AD). Activation of protein kinase C (PKCε) improves several molecular, cellular, physiological, and behavioral endpoints, yet it is not known whether a loss of PKCε activity occurs in the microvascular endothelium in aged and AD hippocampi, whether this loss contributes to microvascular change, or whether activation of PKCε protects against microvascular damage, an early change that induces age-associated memory defect and AD. We investigated the effect of the PKCε activation on microvascular loss in the hippocampus, important for memory storage. In cultured human brain microvascular endothelial cells, tert-butyl hydroperoxide induced oxidative stress and a decrease in manganese superoxide dismutase (MnSOD) mRNA and protein expression that were blocked by the antioxidant drugs. The PKCε activators bryostatin and DCPLA methyl ester increased PKCε, associated with an increase in MnSOD mRNA and its protein as well as vascular endothelial growth factor (VEGF), which was inhibited by the mRNA-stabilizing HuR inhibitors. In rats (>24 months old) and AD transgenic mice Tg2576 (5 months old), bryostatin or DCP-LA prevented a decrease in vascular PKCε, MnSOD, and VEGF and prevented microvascular loss and age-related memory impairment. An autopsy-confirmed AD hippocampus showed a decrease in PKCε and MnSOD mRNAs and their proteins and VEGF as well as in microvascular density compared to non-AD controls. In conclusion, the PKCε activation can rescue a decrease in PKCε, MnSOD, and VEGF posttranscription regulation and alleviate oxidative stress, and in doing so, prevent microvascular loss during aging and AD.
血管内皮功能障碍和毛细血管丧失目前被认为是正常人类衰老和阿尔茨海默病（AD）的主要表型。蛋白激酶C（PKCε）的激活改善了多个分子、细胞、生理和行为学指标，但尚不清楚PKCε活性丧失是否发生在老年和AD海马体的微血管内皮中，这种丧失是否导致微血管变化，或者PKCε的激活是否能防止微血管损伤，而微血管损伤是诱发与年龄相关的记忆缺陷和AD的早期变化。我们研究了PKCε激活对海马体微血管丧失的影响，海马体对记忆存储很重要。在培养的人脑微血管内皮细胞中，叔丁基过氧化氢诱导氧化应激，并导致锰超氧化物歧化酶（MnSOD）mRNA和蛋白表达下降，而抗氧化药物可阻断这种下降。PKCε激活剂苔藓抑素和DCPLA甲酯增加了PKCε，同时伴随着MnSOD mRNA及其蛋白以及血管内皮生长因子（VEGF）的增加，而mRNA稳定化HuR抑制剂可抑制这种增加。在大鼠（>24月龄）和AD转基因小鼠Tg2576（5月龄）中，苔藓抑素或DCP-LA可防止血管PKCε、MnSOD和VEGF的下降，并防止微血管丧失和与年龄相关的记忆障碍。与非AD对照相比，经尸检证实的AD海马体显示PKCε和MnSOD mRNA及其蛋白以及VEGF以及微血管密度均下降。总之，PKCε激活可挽救转录后调控中PKCε、MnSOD和VEGF的下降，减轻氧化应激，并由此防止衰老和AD过程中的微血管丧失。
