Affiliations: [a]
Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA
| [b]
Division of Science and Engineering of University of Guanajuato, Campus Leon, Leon, Guanajuato, Mexico
| [c] Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China, Co-Innovation Center of Neuroregeneration, Nantong University, Jiangsu, China
Correspondence:
[*]
Correspondence to: Khalid Iqbal, Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Rd., Staten Island, NY 10314, USA. Tel.: +1 718 494 5259; Fax: +1 718 494 1080; E-mail: khalid.iqbal.ibr@gmail.com.
Note: [1] These authors contributed equally this work.
Abstract: 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.
Keywords: Alzheimer’s disease, asparagine endopeptidase, ischemia, tau
