Increased neuronal PreP activity reduces amyloid-beta accumulation, attenuates neuroinflammation and improves mitochondrial and synaptic function in Alzheimer disease's mouse model Journal Article
| Authors: | Fang, D.; Wang, Y.; Zhang, Z.; Du, H.; Sun, Q.; Zhong, C.; Wu, L.; Vangavaragu, J. R.; Yan, S. ; Hu, G.; Guo, L.; Rabinowitz, M.; Glaser, E.; Arancio, O.; Sosunov, A. A.; McKhann, G. M.; Chen, J. X.; Yan, S. S. |
| Article Title: | Increased neuronal PreP activity reduces amyloid-beta accumulation, attenuates neuroinflammation and improves mitochondrial and synaptic function in Alzheimer disease's mouse model |
| Abstract: | Accumulation of amyloid-β (Aβ) in synaptic mitochondria is associated with mitochondrial and synaptic injury. The underlying mechanisms and strategies to eliminate Aβ and rescue mitochondrial and synaptic defects remain elusive. Presequence protease (PreP), a mitochondrial peptidasome, is a novel mitochondrial Aβ degrading enzyme. Here, we demonstrate for the first time that increased expression of active human PreP in cortical neurons attenuates Alzheimer disease's (AD)-like mitochondrial amyloid pathology and synaptic mitochondrial dysfunction, and suppresses mitochondrial oxidative stress. Notably, PreP-overexpressed AD mice show significant reduction in the production of proinflammatory mediators. Accordingly, increased neuronal PreP expression improves learning and memory and synaptic function in vivo AD mice, and alleviates Aβ-mediated reduction of long-term potentiation (LTP). Our results provide in vivo evidence that PreP may play an important role in maintaining mitochondrial integrity and function by clearance and degradation of mitochondrial Aβ along with the improvement in synaptic and behavioral function in AD mouse model. Thus, enhancing PreP activity/expression may be a new therapeutic avenue for treatment of AD. © The Author 2015. Published by Oxford University Press. All rights reserved. |
| Keywords: | controlled study; protein expression; unclassified drug; nonhuman; animal cell; mouse; animal tissue; gene overexpression; protein degradation; animal experiment; animal model; in vivo study; enzyme activity; oxidative stress; proteinase; memory; alzheimer disease; learning; amyloid beta protein; protein aggregation; brain cell; synaptic transmission; nervous system inflammation; mitochondrial enzyme; clearance; long term potentiation; brain mitochondrion; mediator release; male; female; priority journal; article; presequence protease |
| Journal Title: | Human Molecular Genetics |
| Volume: | 24 |
| Issue: | 18 |
| ISSN: | 0964-6906 |
| Publisher: | Oxford University Press |
| Date Published: | 2015-09-15 |
| Start Page: | 5198 |
| End Page: | 5210 |
| Language: | English |
| DOI: | 10.1093/hmg/ddv241 |
| PROVIDER: | scopus |
| PMCID: | PMC4550821 |
| PUBMED: | 26123488 |
| DOI/URL: | |
| Notes: | Export Date: 2 October 2015 -- Source: Scopus |
