title: Intramuscular delivery of p75NTR ectodomain by an AAV vector attenuates cognitive deficits and Alzheimer's disease-like pathologies in APP/PS1 transgenic mice.
abstract: The neurotrophin receptor p75 (p75NTR) is a receptor for amyloid-beta (Aβ) and mediates Aβ-induced neurodegenerative signals. The ectodomain of p75NTR (p75ECD) is a physiological protective factor against Aβ in Alzheimer's disease (AD). We have previously demonstrated that the shedding of p75ECD from the cell surface is down-regulated in AD brains and restoration of the p75ECD level in the brain, through intracranial administration of p75ECD by adeno-associated virus vectors, attenuates AD-like pathologies in an AD mouse model. In this study, we further investigated the feasibility and efficacy of peripheral administration of AAV-p75ECD on brain amyloid burden and associated pathogenesis. We found that intramuscular delivery of AAV-p75ECD increased the level of p75ECD in the blood, significantly improved the behavioral phenotype of amyloid precursor protein/PS1 transgenic mice, and reduced brain amyloid burden, attenuated Tau hyperphosphorylation, and neuroinflammation. Furthermore, intramuscular delivery of AAV-p75ECD was well tolerated. Our results indicate that peripheral delivery of p75ECD represents a safe and effective therapeutic strategy for AD. The ectodomain of p75NTR (p75ECD) is a physiological protective factor against amyloid-beta (Aβ) in Alzheimer's disease (AD). Intramuscular delivery of AAV-p75ECD increased the p75ECD levels in the blood, reduced brain amyloid burden through a 'peripheral sink' mechanism and alleviates AD-type pathologies. Peripheral delivery of p75ECD represents a promising therapeutic strategy for AD.
authors.affiliation: Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Qing-Hua
authors.initials: QH
authors.lastname: Wang
authors.affiliation: Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Ye-Ran
authors.initials: YR
authors.lastname: Wang
authors.affiliation: Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Shu-Sheng
authors.initials: SS
authors.lastname: Jiao
authors.affiliation: Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yu-Hui
authors.initials: YH
authors.lastname: Liu
authors.affiliation: Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zeng
authors.affiliation: Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xiu-Qing
authors.initials: XQ
authors.lastname: Yao
authors.affiliation: Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Hua-Dong
authors.initials: HD
authors.lastname: Zhou
authors.affiliation: Division of Health Sciences, School of Pharmacy and Medical Sciences and Sansom Institute, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Xin-Fu
authors.initials: XF
authors.lastname: Zhou
authors.affiliation: Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yan-Jiang
authors.initials: YJ
authors.lastname: Wang
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D003072:Cognition Disorders / Q000235:genetics / Q000628:therapy*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007273:Injections, Intramuscular; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics; D020800:Receptor, Nerve Growth Factor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D053764:Presenilin-1; D020800:Receptor, Nerve Growth Factor; D049452:Green Fluorescent Proteins
keywords: Alzheimer's disease; amyloid-beta; ectodomain; gene therapy; intramuscular delivery; p75NTR