Increased neuronal PreP activity reduces Aβ 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.

• Authors: Du Fang, Yongfu Wang, Zhihua Zhang, Heng Du, Shiqiang Yan, Qinru Sun, Changjia Zhong, Long Wu, Jhansi Rani Vangavaragu, Shijun Yan, Gang Hu, Lan Guo, Molly Rabinowitz, Elzbieta Glaser, Ottavio Arancio, Alexander A Sosunov, Guy M McKhann, John Xi Chen, Shirley ShiDu Yan
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 24 Issue 18 Pg. 5198-210 (Sep 15 2015) ISSN: 1460-2083 [Electronic] England
• PMID: 26123488 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Amyloid beta-Peptides
• Inflammation Mediators
• Serine Endopeptidases

Topics

• Alzheimer Disease (metabolism, physiopathology)
• Amyloid beta-Peptides (metabolism)
• Animals
• Behavior, Animal
• Cells, Cultured
• Cognition
• Disease Models, Animal
• Gene Expression
• Inflammation Mediators (metabolism)
• Mice
• Mice, Transgenic
• Mitochondria (metabolism)
• Neurons (metabolism)
• Oxidative Stress
• Protein Aggregation, Pathological (metabolism)
• Proteolysis
• Serine Endopeptidases (genetics, metabolism)
• Synapses (metabolism)