Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
Division of Science and Engineering of University of Guanajuato, Campus Leon, Leon, Guanajuato, Mexico.
J Alzheimers Dis. 2018;63(2):821-833. doi: 10.3233/JAD-170715.
Dementias including Alzheimer's disease (AD) are multifactorial disorders that involve several different etiopathogenic mechanisms. Cerebral ischemia has been suspected in the altered regulation of protein kinases and phosphatases that leads to hyperphosphorylation of tau and further neurofibrillary pathology, a key hallmark of AD and related neurodegenerative diseases. However, the deregulation of these enzymes and their relationship with ischemia and AD remain unclear. Previously, we reported a mechanism by which the lysosomal enzyme asparagine endopeptidase (AEP) is associated with brain acidosis and AD. In this study, we subjected mice to middle cerebral artery occlusion and found that compared with wild type mice, the ischemia-induced brain injury and motor deficit in AEP-knockout mice are reduced, probably because ischemia activates AEP. AEP cleaves inhibitor 2 of protein phosphatase 2A (I2PP2A), which translocates from the neuronal nucleus to the cytoplasm and produces hyperphosphorylation of tau through inhibition of PP2A. These findings suggest a possible mechanism of tau pathology associated with ischemia.
包括阿尔茨海默病（AD）在内的痴呆症是一种多因素疾病，涉及几种不同的病因发病机制。脑缺血被怀疑与蛋白激酶和磷酸酶的调节异常有关，导致 tau 的过度磷酸化，并进一步引发神经纤维缠结病理，这是 AD 和相关神经退行性疾病的一个关键标志。然而，这些酶的失调及其与缺血和 AD 的关系仍不清楚。之前，我们报道了溶酶体酶天冬酰胺内肽酶（AEP）与脑酸中毒和 AD 相关的机制。在这项研究中，我们使小鼠发生大脑中动脉闭塞，发现与野生型小鼠相比，AEP 基因敲除小鼠的缺血性脑损伤和运动功能障碍减轻，这可能是因为缺血激活了 AEP。AEP 可切割蛋白磷酸酶 2A 的抑制剂 2（I2PP2A），后者通过抑制 PP2A 从神经元核转位到细胞质，导致 tau 的过度磷酸化。这些发现提示了与缺血相关的 tau 病理的一种可能机制。
