title: 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.affiliation: Department of Pharmacology and Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA.
authors.forename: Du
authors.initials: D
authors.lastname: Fang
authors.affiliation: Department of Pharmacology and Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA.
authors.forename: Yongfu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA, School of Life Sciences, Beijing Normal University, Beijing 100871, China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA.
authors.forename: Heng
authors.initials: H
authors.lastname: Du
authors.affiliation: Taub Institute for Research on Alzheimer's disease and the Aging Brain, New York, NY 10032, USA.
authors.forename: Shiqiang
authors.initials: S
authors.lastname: Yan
authors.affiliation: Department of Pharmacology and Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA.
authors.forename: Qinru
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Department of Pharmacology and Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA.
authors.forename: Changjia
authors.initials: C
authors.lastname: Zhong
authors.affiliation: Department of Pharmacology and Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA.
authors.forename: Long
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Pharmacology and Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA.
authors.forename: Jhansi Rani
authors.initials: JR
authors.lastname: Vangavaragu
authors.affiliation: Department of Pharmacology and Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA.
authors.forename: Shijun
authors.initials: S
authors.lastname: Yan
authors.affiliation: Department of Pharmacology and Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
authors.affiliation: Department of Pharmacology and Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Guo
authors.affiliation: Taub Institute for Research on Alzheimer's disease and the Aging Brain, New York, NY 10032, USA.
authors.forename: Molly
authors.initials: M
authors.lastname: Rabinowitz
authors.affiliation: Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Glaser
authors.affiliation: Taub Institute for Research on Alzheimer's disease and the Aging Brain, New York, NY 10032, USA.
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
authors.affiliation: Department of Neurosurgery, Physicians & Surgeons College of Columbia University, New York, NY 10032, USA and.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Sosunov
authors.affiliation: Department of Neurosurgery, Physicians & Surgeons College of Columbia University, New York, NY 10032, USA and.
authors.forename: Guy M
authors.initials: GM
authors.lastname: McKhann
authors.affiliation: Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
authors.forename: John Xi
authors.initials: JX
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Toxicology, Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA, shidu@ku.edu.
authors.forename: Shirley ShiDu
authors.initials: SS
authors.lastname: Yan
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal; D002478:Cells, Cultured; D003071:Cognition; D004195:Disease Models, Animal; D015870:Gene Expression; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D018384:Oxidative Stress; D066263:Protein Aggregation, Pathological / Q000378:metabolism*; D059748:Proteolysis; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D018836:Inflammation Mediators; D012697:Serine Endopeptidases