Martín-Segura Adrián, Casadomé-Perales Álvaro, Fazzari Pietro, Mas José Manuel, Artigas Laura, Valls Raquel, Nebreda Angel R, Dotti Carlos G
Department of Molecular Neuropathology, Centro de Biología Molecular Severo Ochoa, CSIC/UAM, Madrid, Spain.
Albert Einstein College of Medicine, Bronx, NY, United States.
Front Neurol. 2019 Jun 25;10:675. doi: 10.3389/fneur.2019.00675. eCollection 2019.
Numerous studies suggest that the increased activity of p38MAPK plays an important role in the abnormal immune and inflammatory response observed in the course of neurodegenerative diseases such as Alzheimer's disease. On the other hand, high levels of p38MAPK are present in the brain during normal aging, suggesting the existence of mechanisms that keep the p38MAPK-regulated pro-inflammatory activity within physiological limits. In this study, we show that high p38MAPK activity in the hippocampus of old mice is in part due to the reduction in membrane cholesterol that constitutively occurs in the aging brain. Mechanistically, membrane cholesterol reduction increases p38MAPK activity through the stimulation of a subset of tyrosine kinase receptors (RTKs). In turn, activated p38MAPK increases the expression and activity of the phosphatase DUSP2, which is known to reduce the activity of different MAPKs, including p38MAPK. These results suggest that the loss of membrane cholesterol that constitutively occurs with age takes part in a negative-feedback loop that keeps p38MAPK activity levels within physiological range. Thus, conditions that increase p38MAPK activity such as cellular stressors or that inhibit DUSP2 will amplify inflammatory activity with its consequent deleterious functional changes.
大量研究表明，p38丝裂原活化蛋白激酶（p38MAPK）活性增加在诸如阿尔茨海默病等神经退行性疾病过程中观察到的异常免疫和炎症反应中起重要作用。另一方面，在正常衰老过程中大脑中存在高水平的p38MAPK，这表明存在将p38MAPK调节的促炎活性维持在生理限度内的机制。在本研究中，我们表明老年小鼠海马中p38MAPK的高活性部分归因于衰老大脑中持续发生的膜胆固醇减少。从机制上讲，膜胆固醇减少通过刺激一部分酪氨酸激酶受体（RTK）来增加p38MAPK活性。反过来，活化的p38MAPK增加磷酸酶DUSP2的表达和活性，已知DUSP2可降低包括p38MAPK在内的不同丝裂原活化蛋白激酶的活性。这些结果表明，随着年龄增长而持续发生的膜胆固醇丧失参与了一个负反馈回路，该回路将p38MAPK活性水平维持在生理范围内。因此，增加p38MAPK活性的条件（如细胞应激源）或抑制DUSP2的条件将放大炎症活性及其随之而来的有害功能变化。
